At 89, he had been the oldest person in the Senate and the last remaining World War II veteran.
He served nearly three decades in the Senate in two stints, beginning with an upset victory in 1982 over Republican Rep. Millicent Fenwick, the pipe-smoking, pearl-wearing patrician who was the model for the cartoon character Lacey Davenport in "Doonesbury."
Possessed with neither a dynamic speaking style nor a telegenic face, he won his last race in 2008 at age 84, becoming the first New Jersey person ever elected to five Senate terms.
"People don't give a darn about my age," Lautenberg said then. "They know I'm vigorous. They know I've got plenty of energy."
Over the years, Lautenberg worked to secure hundreds of millions of dollars for mass transit projects in New Jersey and became an ardent defender of Amtrak.
He was the author of a 1984 law that threatened to withhold federal highway money from states that did not adopt a drinking age of 21, a measure that passed amid rising alarm over drunken driving. At the time, some states allowed people as young as 18 drink.
By 1988, every state was in compliance with the law, which has been widely credited with reducing highway deaths.
A former smoker, Lautenberg was one of two prime sponsors of the 1989 law that banned smoking on all domestic flights of less than six hours, one of several anti-smoking laws he championed and one that helped pave the way for today's numerous restrictions on where people can light up.
Lautenberg had announced in February that he would not seek a sixth term. A longtime advocate of gun control, he returned to the Senate in April despite being in poor health for several votes on gun legislation favored by President Barack Obama, most Democrats and a handful of Republicans. He voted in favor of enhanced background checks for gun purchases and to reinstate a ban on assault-style weapons. Both measures failed.
Wheelchair-bound, he received warm greetings from several colleagues on the Senate floor. He also voted to move along the nomination of a new EPA commissioner, Gina McCarthy.
"Frank was a passionate public servant who was not afraid to fight and vote for what he believed in. He loved the Senate," said Sen. Patty Murray, D-Wash. "He retired once but service called him back, and until the very end of his life, Frank made the trip from New Jersey to D.C. to fight for the issues he believed in and the people he represented. He gave everything he had to public service."
Republican Gov. Chris Christie, whom the Democrat Lautenberg frequently criticized, will appoint a successor and a special election will determine a replacement. Newark Mayor Cory Booker had announced his intention to run and had raised some $2 million.
Along with Lautenberg's legislative accomplishments, he had a string of electoral coups, including his upset over Fenwick, whom he called "the most popular candidate in the country," and a victory in a strange, abbreviated, back-from-retirement campaign 20 years later.
He initially retired in 2000 after 18 years in the Senate, saying he did not have the drive to raise money for a fourth campaign. He served on the boards of three companies, two graduate schools and the U.S. Holocaust Memorial Museum.
But New Jersey Democrats recruited Lautenberg out of retirement in September 2002 as an 11th-hour replacement for Robert Torricelli, Lautenberg's longtime rival, who had abandoned his re-election bid just five weeks before Election Day.
Republicans went to court to prevent what they called the Democratic Party's ballot "switcheroo." When that failed, they attacked Lautenberg as a political relic ill-suited for dangerous times.
But Lautenberg surged to an easy win over Republican Douglas Forrester and returned to the Senate in 2003 at age 78, resuming his role as a leading liberal, and he made it clear that his return to office was no mere cameo.
When the Democrats regained a Senate majority in 2007, he returned to the powerful Appropriations Committee, on which he had served for 15 years. Then, in the fall of 2008, he beat back a Democratic primary challenge.
He was back in the headlines in December that year this time as an apparent victim.
After Wall Street money manager Bernard Madoff was accused of running a $50 billion fraud scheme, Lautenberg's family foundation said the bulk of its investments were managed by him. A lawyer for the foundation declined to discuss the amount of any possible losses, but tax records in 2006 indicated Madoff managed more than 90 percent of the foundation's nearly $14 million in assets.
Lautenberg first gained prominence as chairman and CEO of Automatic Data Processing, a New Jersey-based payroll services company he had founded with two friends in 1952. It became one of the largest such companies in the world.
He was first elected to the Senate in 1982, during the presidency of Ronald Reagan. Working his way up the seniority ladder, Lautenberg managed to carve out influence on the environment and transportation, two issues that matter greatly to New Jersey, the nation's most densely populated state.
Before Republicans won control of the Senate in the 1994 elections, Lautenberg was chairman of key subcommittees responsible for transportation appropriations and the Superfund pollution cleanup program. He became the ranking Democrat on those panels after 1994.
From those posts, he worked to secure hundreds of millions of dollars for mass transit projects in the state, which he said would reduce pollution and traffic congestion. He also was a leading defender of Amtrak, the nation's passenger rail system.
In 1984, as a novice lawmaker and member of the minority chamber in the Senate, Lautenberg wrote a bill to withhold federal highway funds from states that did not set 21 as a minimum age to buy and possess alcohol.
After the federal voting age was lowered to 18 in 1971, many states followed suit by setting minimum drinking ages at 18 to 20.
By the early 1980s, the problem of drunken driving by teenagers was getting widespread attention. Reagan signed the bill, and by 1988, every state had a legal drinking age of 21.
Lautenberg often attacked tobacco companies' advertising tactics. During a 1989 debate over smoking, when tobacco-state lawmakers asked what would become of tobacco farmers, Lautenberg scoffed, "Grow soybeans or something."
Another frequent target was the gun industry. "Common sense tells you that there are more than enough dangerous weapons on the streets," said Lautenberg, who sponsored numerous gun-control measures, a few of which were enacted.
He also spent much of his political career pushing for funding for Superfund, a program that pays for cleanup of environmentally hazardous sites.
Lautenberg was a reliable vote for traditional Democratic policies, though he bucked President Bill Clinton in 1993 on the budget because he said it raised taxes and didn't cut spending enough. He also voted against Clinton on the North American Free Trade Agreement, opposed by the staunch labor allies Lautenberg had come to depend on.
Later in his career, he became a foil for Christie.
In 2012, Christie called Lautenberg a "partisan hack" and an "embarrassment" and said it was time for him to retire. Lautenberg called Christie "the name-calling governor" and, in one speech, "the king of liars."
Lautenberg had health problems in recent years. He had the flu and missed the Senate's Jan. 1 vote to avoid the so-called fiscal cliff of rising taxes and falling government spending, then missed several votes two months later because of leg pain. A chest cold kept him from attending a May 29 tribute in New York honoring him for his contributions to the Jewish community and Israel.
He had been diagnosed in February 2010 with B-cell lymphoma of the stomach and underwent chemotherapy treatments until he was declared in June 2010 to be free of cancer. He worked between the treatments.
The diagnosis came just days after the death of Sen. Robert Byrd of West Virginia, making Lautenberg the oldest member of the Senate.
For his first 14 years in the Senate, he was often in the shadow of New Jersey's other, better known senator, Bill Bradley, a former pro basketball player and 2000 presidential candidate. But he proved a formidable and bruising foe.
Running for an open Senate seat in 1982, Lautenberg won 51 percent of the vote against Fenwick. The win, financed largely with $3 million of Lautenberg's own fortune, was a shocker.
Fenwick was 72 when Lautenberg questioned her capacity to serve in the Senate. On the campaign trail, he criticized her "capability" to be a senator, but some observers seemed to think he was going after her age a fact that was noted 26 years later when he ran for re-election at age 84.
"It's hard when your own words come back to haunt you, isn't it, Mr. Lautenberg?" said an ad for his Democratic primary opponent, U.S. Rep. Robert Andrews, whom he defeated handily before beating former U.S. Rep. Dick Zimmer in the general election.
After Lautenberg won the 1982 election, Nicholas Brady, who had been appointed to serve the remainder of the previous term, resigned early to give Lautenberg valuable seniority over other new senators. He was sworn in Dec. 27, 1982, by a federal judge from Denver while he was vacationing in Vail, Colo.
In 1988, Lautenberg faced Pete Dawkins, a handsome Heisman Trophy winner who attended the U.S. Military Academy and went on to become a brigadier general and successful executive. Lautenberg's campaign assailed Dawkins as an out-of-touch carpetbagger and ran ads urging Dawkins, "Be Real, Pete." Lautenberg won with 54 percent of the vote.
He won a third term in 1994 against Republican Garabed "Chuck" Haytaian, despite the GOP gains nationwide that overturned Democratic majorities in the Senate and House and Haytaian's criticism of Lautenberg as a "silent senator."
In his unusual five-week return to campaigning in 2002, Lautenberg persevered with a steady, risk-averse campaign that portrayed him as a "serious senator" for "serious times" a year after the 9/11 terrorist attacks.
Republicans focused on Lautenberg's liberal voting record, notably his opposition to the death penalty, development of a missile defense system and the 1991 resolution authorizing force against Iraq.
Born in urban Paterson, N.J., the son of Polish and Russian Jewish immigrants, Lautenberg never forgot his roots. He often recounted what government did for him and what it could have done to help his widowed mother as she struggled to pay his father's medical bills.
"We want to help. That's government's role," Lautenberg said during his successful bid for re-election in 1994.
He was educated at Nutley High School and served in the Army Signal Corps during World War II. With the help of the G.I. bill, he received an undergraduate degree in economics from Columbia University.
Lautenberg, who lived in Cliffside Park, N.J., is survived by his wife, Bonnie, and four children from his first marriage, which ended in divorce in 1988.
Associated Press writer Andrew Taylor contributed to this report.