US President George Bush released a statement late on Friday saying, "This weekend the American people turn our thoughts to images of 40 years ago, and to the good and graceful life that ended on November 22, 1963."
On that brisk, sun-bathed Texas morning, the country's youngest president was cut down by sniper bullets as he and his wife, Jackie, rode in an open-top limousine through the crowd-lined streets of Dallas in a campaign motorcade.
Five years later, his younger brother Robert, then a Democratic presidential hopeful, was also felled by an assassin's bullet, setting the stage for a macabre litany of grief and conspiracy theories that still haunts the Kennedy clan.
Lee Harvey Oswald, a troubled former Marine who apparently defected to the Soviet Union in 1959 and returned with a Russian bride two years later, was arrested and charged with firing the fatal rifle shots from the sixth floor of the Texas School Book Depository.
Two days later, as he was being transferred between jails, Oswald was fatally shot by Jack Ruby, owner of a local nightclub with Mafia links, who was convicted of murder and died in prison.
A blue-ribbon commission headed by former Supreme Court Chief Justice Earl Warren concluded Oswald had acted alone. But theories of a conspiracy, and a second gunman, persisted.
A recently released film of the assassination, taken from a different angle, appeared to lend credence to the second-shooter theory, showing Kennedy's head being hit by a bullet apparently fired from the right front of his limousine. Oswald had fired from the rear.
The presidential motorcade rolls through the streets of Dallas
But the ABC television network is to air a report later this week confirming that Oswald acted alone.
If there was a conspiracy, who was behind it? Theories abound: the Russians, the Mafia, right-wing fanatics, Cuba, even JFK's vice president and successor, Lyndon Johnson. None has held water.
JFK is buried in Arlington National Cemetery across the Potomac River from the nation's capital. The Kennedy family has not said whether it will hold a memorial ceremony there on Saturday.
"The Kennedy family always preferred President Kennedy to be remembered on his birthday rather than on the day he died," said Gary Mack, curator of the Sixth Floor Museum in Dallas, dedicated to preserving in minute detail the events of that fateful Friday morning.
Mack, then a high school student, was having breakfast in the school cafeteria when he heard the news.
"The assistant principal came in. He stood next to our table. He didn't say a word. He looked around, and I noticed his lips were trembling," Mack recalled.
Darwin Payne, a retired communications professor in Dallas, was a cub reporter for a local newspaper at the time. For him, news of the shooting "came from our police reporter, who was monitoring the police dispatcher's radio.
"I walked and ran ... to Dealey Plaza (the site of the shooting). I did not know where the president was hit, how exactly it happened. There were anguished people, crying...
JFK's family mourn his passing
"I started looking for eyewitnesses. I found one who said her boss had taken pictures, film. He was Abraham Zapruder. He was in the very next building. She took me to his office..."
The film Zapruder shot and his testimony before the Warren Commission were critical to the commission's inquiry.
Today, the city of Dallas, try as it may to put the tragedy to rest, has become a repository of its memorabilia. The book depository is a national museum. The exact spot where Kennedy was shot has become a historic site, unchanged since 1963.
Despite historians' attempts to portray him with all of his blemishes - including being chronically ill and dependent on medication, linked to the Mafia, and an inveterate womaniser - JFK remains an iconic myth and legend, indelibly imbued on the national psyche.
For the surviving Kennedy brother, Senator Ted Kennedy of Massachusetts, the memory of John and Robert lives on.
"They continue to inspire me," he said recently. "They were my heroes.