Veteran US Senator Edward Kennedy, the brother of ex-President John F Kennedy, has died at the age of 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 had been a dominant force in liberal US politics for almost half a century.
Recently he was an active supporter of President Barack Obama.
He has championed issues like healthcare and education.
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 also a fierce critic of the Bush administration, in particular over Iraq and the prisoner abuse scandal.
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."
The Kennedy family announced his 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
"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.