Abandoning generations of US attempts to cut Cuba from the outside world, the US president, First Lady Michelle Obama and their two daughters left Andrews Air Force Base for the short flight to Havana where they were spending three days.
Accompanying them was the first lady's mother, Marian Robinson.
It was not only the first visit by a sitting US president since Fidel Castro's guerrillas overthrew the US-backed government of Fulgencio Batista in 1959, but the first since President Calvin Coolidge came 88 years ago.
For Cubans dreaming of escaping isolation and reinvigorating their threadbare economy, the visit has created huge excitement.
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"A president of the United States in Cuba arriving in Havana on his Air Force One," wrote popular Cuban writer Leonardo Padura on the Cafefuerte blog.
"Never in my dreams or nightmares could we have imagined that we'd see such a thing."
Early Sunday cleaners swept the narrow, cobbled streets where Obama was due to stroll later and police, especially plainclothes, were out in large numbers.
But minutes before Obama took off for Cuba, police in Havana arrested dozens of people from a banned group demanding greater human rights, AFP reporters said.
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The United States spent decades trying to topple Cuba's communist government.
Washington attempted economic strangulation, the failed 1961 Bay of Pigs invasion, and CIA assassination plots against Fidel Castro -- including the legendary, but unproven story of sending him an exploding cigar.
Although a decades-long US economic embargo remains in place -- and can only be removed by the Republican-controlled Congress -- large cracks in the sanctions regime are appearing.
Obama hopes that a host of incremental and seemingly technical steps will open Cuba's economy, transforming the island economically and politically, backers of the policy say.
Lawmakers including House Minority Leader Nancy Pelosi were with Obama, while a delegation of political and business leaders was traveling separately.
In the latest such move, the US government gave the home rental platform Airbnb a green light to accept bookings in Cuba from non-American customers.
Earlier, US group Starwood Hotels & Resorts Worldwide said it had signed three hotel deals in Cuba, a first for any hospitality company since the revolution of 1959.
Cuba's regime, which for decades defined itself as the people's bulwark against the Yankee enemy, has bowed to the fact that Cubans would rather do business than make war.