At 89, he was the oldest person in the Senate and the last of 115 World War II veterans to serve there.
"He improved the lives of countless Americans with his commitment to our nation's health and safety," President Barack Obama said in a statement, "from improving our public transportation to protecting citizens from gun violence to ensuring that members of our military and their families get the care they deserve."
The Senate observed a moment of silence in Lautenberg's memory, and at the White House the flag was lowered to half-staff.
Lautenberg 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 politician 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, he was a reliable Democratic vote on such issues as unions, guns and the environment. A native of one of the most congested and heavily industrialized and polluted states, he worked to secure hundreds of millions of dollars for mass transit projects, ardently defended Amtrak and pushed for money for the Superfund toxic-waste cleanup program.
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 to 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. The measure helped pave the way for today's numerous restrictions on where people can light up.
Despite poor health that left him in a wheelchair, he returned to the Senate in April for several votes on gun legislation. He voted in favor of enhanced background checks for gun purchases and reinstatement of a ban on assault-style weapons. Both measures failed.
Lautenberg had announced earlier this year that he would not seek another term in 2014, and Newark Mayor Cory Booker, a fellow Democrat, said he would run for the seat.
Senate Republican leader Mitch McConnell called Lautenberg "a patriot whose success in business and politics made him a great American success story and a standout even within the fabled Greatest Generation."
Republican Gov. Chris Christie, who frequently tangled with Lautenberg, said: "I think the best way to describe Frank Lautenberg and the way he would probably want to be described to all of you today is as a fighter. Sen. Lautenberg fought for the things he believed in, and sometimes he just fought because he liked to."
"I give him praise on a life well-lived," the governor added.
Christie will appoint an interim successor. A special election could be held in the fall, or the appointed successor could serve until the 2014 election. Because New Jersey law is vague on the matter, the courts might have to sort it out.
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 two decades 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 2002 as a replacement for Robert Torricelli, who had abandoned his re-election bid just five weeks before Election Day in a campaign finance scandal.
Republicans went to court to prevent the ballot "switcheroo." When that failed, they attacked Lautenberg as a political relic ill-suited for dangerous times.
But Lautenberg surged to an easy victory over Republican Douglas Forrester and returned to the Senate in 2003 at age 78, resuming his role as a leading liberal.
He was in the headlines in December 2008 this time as an apparent victim.
After Bernard Madoff was accused of 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 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 made his fortune 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.
During his first stint in the Senate, he was often in the shadow of New Jersey's other senator, Bill Bradley, a former pro basketball player and 2000 presidential candidate. But he proved a formidable and bruising foe, carving out influence on the environment and transportation, two issues that matter greatly to New Jersey, the most densely populated state.
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 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 "the king of liars."
Lautenberg had been diagnosed in February 2010 with B-cell lymphoma of the stomach and underwent chemotherapy until he was declared cancer-free in June 2010.
During his first Senate election victory, in 1982, Fenwick was 72, and Lautenberg had questioned her "capability" to serve. Some observers seemed to think he was going after her age something that was used against him decades later when he ran at 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.
Born in urban Paterson, N.J., the son of Polish and Russian Jewish immigrants, Lautenberg 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 in 1994.
He served in the Army Signal Corps during World War II. With the help of the GI Bill, he attended Columbia University and received a degree in economics.
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.