The agreement would require both sides to reduce their arsenals of long-range nuclear weapons by about a third, from 2,200 now to 1,500 each. The pact, replacing and expanding a 1991 treaty that expired in December, was a gesture toward improved U.S.-Russian relations that have been badly frayed.
The reductions would still leave both sides with immense arsenals -- and the ability to easily annihilate each other.
"In many ways, nuclear weapons represent both the darkest days of the Cold War, and the most troubling threats of our time. Today, we have taken another step forward in leaving behind the legacy of the 20th century while building a more secure future for our children," Obama said at the White House.
In Russia, Medvedev's spokeswoman Natalya Timakova told the Interfax news agency, "This treaty reflects the balance of interests of both nations."
Both sides would have seven years after the treaty's ratification to carry out the approximately 30 percent reduction in long-range nuclear weapons. The agreement also calls for smaller cuts to warheads and bombs based on planes, ships and land.
"We have turned words into action. We have made progress that is clear and concrete. And we have demonstrated the importance of American leadership -- and American partnership -- on behalf of our own security, and the world's," Obama said.
Though the agreement must still be ratified by the Senate and the Russian Duma before it takes effect, Obama and Medvedev plan to sign it next month in Prague, the city where last April, Obama delivered his signature speech on arms control.
For his administration, a major value of the treaty is in setting the stage for potential further successes.
Secretary of State Hillary Rodham Clinton, standing with Defense Secretary Robert Gates alongside Obama, noted next month's international meeting of leaders on nuclear proliferation being hosted by Obama in Washington, focused on preventing the spread of nuclear weapons to terrorists and rogue states.
"We come with more credibility, Russia comes with more credibility, having negotiated this treaty," she said.
Ratification of the treaty will require 67 votes, or two-thirds of the U.S. Senate. Clinton, asked whether such a margin could be achieved given the recent fierce partisan battles and close votes over health care, said it could.
"National security has always produced large bipartisan majorities, and I see no reason why this should be any different," she said. "The vast majority of senators will see that this is about America's national interest, it's not about politics."
Speaking in the White House briefing room, Obama said the treaty by the globe's two largest nuclear powers would "send a clear signal that we intend to lead" the rest of the world in reducing the nuclear threat.
Clinton noted that the U.S. and Russia still possess more than 90 percent of the world's nuclear weapons. "We do not need such large arsenals to protect our nation," she said.
She emphasized the verification mechanism in the treaty, a key demand of the U.S. that was resisted by Russia and was one of the sticking points that delayed completion of the deal. It will "reduce the chance for misunderstandings and miscalculations," she told reporters.
Adm. Mike Mullen, chairman of the Joint Chiefs of Staff, emphasized the support of the military for the arsenal reductions in the agreement, saying that commanders around the world "stand solidly behind the treaty."
Friday's remarks by administration officials were aimed toward the Senate and marked the beginning of a long and probably tough campaign to win ratification.