Castro's brother Raul, who is likely to assume control on Sunday, has raised expectations for modest reforms since he took over as acting president last year.
Obama went the furthest, saying: "If the Cuban leadership begins opening Cuba to meaningful democratic change, the United States must be prepared to begin taking steps to normalize relations and to ease the embargo of the last five decades," he said in a statement.
Obama has criticized a policy of continuing to isolate Cuba while other candidates have said they would insist on significant reforms to take place, said Tomas Bilbao, executive director of the nonprofit Washington-based Cuba Study Group.
"It does sound a bit different than what you hear from other candidates - what he's saying is, the U.S. government needs to be prepared to respond to incremental reforms in Cuba," Bilbao said.
Republican candidates took a harder line, saying there is little indication so far that Castro's departure would spark the sea change needed before the U.S eases decades-long trade and tourism restrictions against Cuba.
The Democrats sparred last year when Obama, in a debate, said he would meet with Castro and other leaders of renegade nations without preconditions; Clinton called that approach naive. Obama also broke with other candidates by saying last year that he would ease restrictions on family-related travel and remittances, or money that Cuban-Americans can send home.
On Tuesday, however, Clinton struck the same tone about Castro's resignation.
"Certainly, the people of the U.S. would need a new government to talk about what needs to happen if that new government takes some action that demonstrates they are willing to change," Clinton said at a diner Tuesday in Parma, Ohio. "So we're hoping to see some evidence of that. It is a very stark reminder that even if you've been in power for 50 years, you cannot hold onto power forever."
Republicans, on the other hand, insisted that significant benchmarks be met before there is any response from the U.S.
Republican John McCain called it "a great opportunity for Cuba to make a transition to a democracy, to empty their political prisons, to invite human rights organizations into the country and begin the transition to a free and open society."
Lifting the U.S. embargo on travel and trade before those conditions are met would only prop up a new regime, McCain said at a news conference in Brookfield, Wis.
"So we have to be absolutely confident that the transition to a free and open democracy is being made before we provide that additional aid and assistance," said McCain, the Arizona senator and GOP nominee-in-waiting.
Mike Huckabee, the former Arkansas governor who is still in the GOP race, was less diplomatic.
"Until Fidel Castro is dead, there can be no significant movement towards reform in Cuba," Huckabee said in a statement. "Raul Castro has proven that he's as much a tyrant and dictator as his brother Fidel. Simply providing more power to another dictator does nothing to promote freedom and democracy to the Cuban people."