Senator Edward Kennedy has died aged 77, after battling a brain tumour.
The brother of John F Kennedy and Democrat grandee, nicknamed 'Ted', died at his home in Hyannis Por, Massachusetts. He was diagnosed with brain cancer in May of 2008.
Mr Kennedy's family announced his death in a brief statement released early today.
"We've lost the irreplaceable center 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," a family statement said.
"We thank everyone who gave him care and support over this last year, and everyone who stood with him for so many years in his tireless march for progress toward justice."
For nearly a half-century in the Senate, Mr Kennedy was a dominant voice on health care, civil rights, war and peace, and more.
Mr Kennedy was elected to the Senate in 1962, when his brother John was president, and served longer than all but two senators in history.
Over the decades, Mr Kennedy put his imprint on every major piece of social legislation to clear the Congress.
President Obama awarded Kennedy with the Medal of Freedom last week, the highest honor given to a civilian.
In a recent interview with The Associated Press, Kennedy's son, Rhode Island Democratic congressman Patrick Kennedy, said his father had defied the predictions of doctors by surviving more than a year with his fight against brain cancer.
The younger Kennedy said that gave family members a surprise blessing, as they were able to spend more time with the senator and to tell him how much he had meant to their lives.
The younger Kennedy said his father's legacy was built largely in the Senate.
"He has authored more pieces of major legislation than any other US senator," Patrick Kennedy said in the interview.
"He is the penultimate senator. I don't need to exaggerate when I talk about my father. That's the amazing thing. He breaks all the records himself."