Veteran US Senator Edward Kennedy, the brother of former President John F Kennedy, has died at 77, after a long battle with a brain tumour.
He became a Democratic Massachusetts senator in 1962, replacing his brother when he resigned to become president, and was re-elected seven times.
Senator Kennedy was a dominant force in US politics for almost 50 years.
President Barack Obama, of whom he was an active supporter, said he was "heartbroken" to hear of his death.
"An important chapter in our history has come to an end," he said. "Our country has lost a great leader, who picked up the torch of his fallen brothers and became the greatest United States senator of our time."
Senator Kennedy had championed issues such as education and healthcare, central to Mr Obama's first term.
The liberal lion's mighty roar may now fall silent, but his dream shall never die
Harry Reid
Senate Majority leader
Senator Edward Kennedy: Your comments
Kennedy family statement
In quotes: Edward Kennedy tributes
In 2006, Time magazine named him as one of America's "Ten Best Senators" saying that he had "amassed a titanic record of legislation affecting the lives of virtually every man, woman and child in the country".
The BBC's Richard Lister in Washington says Senator Kennedy, known affectionately as Teddy, will be remembered as one of the most effective and popular legislators in American history.
Our correspondent says he was also skilled at forging alliances across party lines: pushing an education initiative with President George W Bush, and immigration reform with Republican John McCain.
But he was a fierce critic of the Bush administration, in particular over Iraq and the prisoner abuse scandal.
He will also be remembered as a staunch supporter of Irish Republicanism - at one time calling for British troops to leave Northern Ireland - although he was later involved in the peace process leading to the Good Friday Agreement.
This is the cause of my life... Now the issue has more meaning for me - and more urgency - than ever before, but it's always been deeply personal, because the importance of healthcare has been a recurrent lesson throughout most of my 77 years
Edward Kennedy
Senator Kennedy's Newsweek article on healthcare, July 2009
Senate Majority leader Harry Reid said the Kennedy family and the Senate had "together lost our patriarch".
"The liberal lion's mighty roar may now fall silent, but his dream shall never die," he said.
UK Prime Minister Gordon Brown said that Senator Kennedy would be "mourned not just in America but in every continent".
"Even facing illness and death, he never stopped fighting for the causes which were his life's work. I am proud to have counted him as a friend."
'Joyous light'
Dawn broke over Washington's Capitol building, the home of the Senate, with the US flag flying at half mast.
The Kennedy family announced Senator Kennedy's death in a brief statement in the early hours of Wednesday.
EDWARD MOORE KENNEDY
1932 Born, youngest of nine children
1962 Becomes country's youngest senator
1963, 1968 Brothers President John F Kennedy and Senator Robert F Kennedy both assassinated
1969 "Chappaquiddick incident" - Kennedy flees scene after road crash in which his young passenger dies
1980 Runs unsuccessfully for Democratic nomination against sitting President Jimmy Carter
Obituary: Edward Kennedy
In pictures: Edward Kennedy
Edward Kennedy - a political life
"Edward M Kennedy, the husband, father, grandfather, brother and uncle we loved so deeply, died late Tuesday night at home in Hyannis Port (Massachusetts)," the statement said.
"We've lost the irreplaceable centre of our family and joyous light in our lives, but the inspiration of his faith, optimism, and perseverance will live on in our hearts forever."
Edward Kennedy was the only one of four brothers to die a natural death.
His brother Joseph was killed in an air crash in World War II, and both President John F Kennedy and presidential hopeful Robert F Kennedy were assassinated in the 1960s.
He was widely expected to be the next Kennedy in the White House, but he was never able to fully overcome the scandal caused in 1969, when he drove a car off a bridge at Chappaquiddick near his home, killing his female passenger.
The incident helped derail his only presidential bid, more than a decade later.
But he remained active in politics right up until his death, famously endorsing Barack Obama for the Democratic nomination during a tight race with Hillary Clinton last year.
At his death, he was the third longest serving senator in US history.
Last week, he asked the Massachusetts governor to change state law to allow a speedy succession when his Senate seat became vacant.
Analysts suggest that Senator Kennedy feared a lengthy gap could deny Democrats a crucial vote on Mr Obama's flagship health reform.
His death comes weeks after that of his older sister, Eunice Kennedy Shriver, on 11 August.
US MEDIA REACTION TO TED KENNEDY'S DEATH
Kennedy was at the center of the most important issues facing the nation for decades, and he did much to help shape them. A defender of the poor and politically disadvantaged, he set the standard for his party on health care, education, civil rights, campaign-finance reform and labor law
Joe Holley writes in The Washington Post on Ted Kennedy's political importance
He was a Rabelaisian figure in the Senate and in life, instantly recognizable by his shock of white hair, his florid, oversize face, his booming Boston brogue, his powerful but pained stride. He was a celebrity, sometimes a self-parody, a hearty friend, an implacable foe, a man of large faith and large flaws, a melancholy character who persevered, drank deeply and sang loudly. He was a Kennedy.
New York Times journalist John M Broder describes the Kennedy effect.
Seared in my memory: When I interned at the Heritage Foundation, I would pop into Mass at Saint Joseph's on the Hill. And I would almost always find myself sitting near Ted Kennedy. He's responsible for things that are deeply offensive to my conscience and diametrically opposed to the teachings of the Catholic faith, and he probably led some people astray by his example. But our faith also teaches that we are all sinners and that there is redemption. He had some incredibly good forces in his life, not least among them his sister, Eunice, who just died. I pray for the repose of his soul. R.I.P. Senator Kennedy.
Kathryn Lean Lopez blogs her tribute at the National Review.
Elected first in 1962, the 77-year-old Massachusetts liberal was rooted in the civil rights and Great Society battles of that decade, but his enduring strength was an ability to renew himself through his mastery of issues and the changing personalities of the Senate. Nowhere was this clearer than in Kennedy's early support of Barack Obama in 2008, when the young Illinois Democrat needed to establish himself against more veteran rivals for the White House. Kennedy not only campaigned for Obama but, at risk to his own health, opened the Democratic National Convention a year ago in Denver and returned to Washington repeatedly last winter to cast needed votes to move the new president's economic recovery agenda.
David Rogers in Politico highlights the veteran senator's lasting political importance.