Veteran US Senator Edward Kennedy, the brother of ex-President John F Kennedy, has died at the age of 77 after battling a brain tumour.
The Democratic Massachusetts senator was diagnosed with a malignant brain tumour in May last year.
He became a member of the Senate in 1962 to replace his brother when he resigned to become president,
and was re-elected seven times.
He has been an active supporter of current President Barack Obama.
Correspondents say Senator Kennedy – universally known as “Teddy” – has been a dominant force in liberal American politics for almost half a century, especially on issues like healthcare and education.
The BBC’s Richard Lister in Washington says he will be remembered as one of the most effective and popular legislators in American history.
Senate Majority leader Harry Reid said the Kennedy family and the Senate had “together lost our patriarch”.
The Kennedy family announced his death in a brief statement in the early hours of Wednesday.
“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.
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.
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.