President Barack Obama called the pact signed Thursday a fresh beginning with Russia and predicted the Senate would ratify the agreement by the end of the year.
"This ceremony is a testament to the truth that old adversaries can forge new partnerships," Obama said in Prague, where he stood grinning with Russian President Dmitry Medvedev following the signing of a treaty that would shrink the one-time rivals' arsenals to their lowest levels since the frightening arms race of the 1960s.
Obama returns to Washington on Friday.
The warheads covered by the treaty are lethal relics of the Cold War, and even with the planned reductions there will be enough firepower on each side to devastate the world many times over. Of more immediate concern are attempts by terrorist groups like al Qaeda and nations such as Iran and North Korea to acquire or use nuclear weapons.
The treaty requires approval by two-thirds of the Senate to take effect.
"It is clearly a legacy issue for the Obama administration," says CBS News foreign affairs analyst Pamela Falk, "but the administration has built in wiggle room on development of weapons to satisfy some conservative critics and, although it will take some time to pass, it is clear that the treaty improves U.S.-Russian relations and will have strong backing from the president himself."
Obama will need 67 votes in a chamber where Democrats control 59 seats in a sour political climate that could tempt Republicans to set aside the nonpartisan deference often given to national security treaties.
"There is a strong history of bipartisanship when it comes to the evaluation of international treaties, particularly arms control treaties," Obama said.
Republicans did not rush to either praise or criticize the treaty. They want Obama to promise it won't undercut the U.S. ability to set up missile defenses to protect against an attack from Iran or North Korea.
They also want assurances that the agreement will preserve what's known as the "nuclear triad" - the nation's ability to deliver nuclear weapons from the air, land and sea.
"The Senate will assess whether or not the agreement is verifiable, whether it reduces our nation's ability to defend itself and our allies from the threat of nuclear armed missiles, and whether or not this administration is committed to preserving our own nuclear triad," said Senate Republican Leader Mitch McConnell.
Republican officials say they won't know the answer to those questions until lawmakers are briefed on the treaty and its technical annexes in detail and convene hearings.
"We'll want to review all of that, have constructive discussions with the administration officials in charge of implementing it and then obviously talk to experts, have hearings and debate in the Senate," Republican Sen. Jon Kyl said.
He added that the president's modernization plan for the nation's nuclear arsenal would also bear on his decision to support or oppose the treaty.
More on Obama's nuclear strategy:
The landmark successor to the 1991 Strategic Arms Reduction Treaty was nearly a year in the making. Called the "New START," it signaled a bold opening in previously soured U.S.-Russia relations. If ratified by both nations' legislatures, it will shrink the limit of nuclear warheads to 1,550 each over seven years, down about a third from the current ceiling of 2,200.
Senate Majority Leader Harry Reid said Thursday that he bets that Republicans won't "play politics" on the issue.
"Strategic arms control treaties similar to this one have historically passed the Senate with strong bipartisan support, and I am confident that this agreement will receive the 67 votes from both sides of the aisle needed for passage," he said in a statement.
The Democrats lost their 60-vote, filibuster-proof margin with the January election of Republican Sen. Scott Brown to fill the late Democrat Edward Kennedy's Massachusetts seat.
Several Senate Republicans, including Kyl and John McCain of Arizona, have said they think Obama has put too many restraints on the nuclear arsenal, which could weaken the nation's defense. Obama this week announced a new strategy that would narrow circumstances under which the weapons would be used.
But the treaty, which would cut back the size of the arsenal, has been less contentious. McCain has supported arms reductions in the past.
Democrats are hoping they can find support from Sen. Richard Lugar, a moderate Republican steeped in nonproliferation issues and the top Republican on the Senate Foreign Relations Committee.
Lugar has said he looks forward to hearings on the matter "so that we can work quickly to achieve ratification of the new treaty."
Obama gave no specific timeline other than by the end of the year. Some administration officials have suggested a vote is more likely after congressional elections in November.