The new pact is only part of the Obama administration's new nuclear strategy. It was signed only days after the White House announced a fundamental shift in its policy on the use of nuclear weapons, calling the acquisition of atomic arms by terrorists or rogue states a worse menace than the Cold War threat of mutual annihilation.
Other U.S. nuclear initiatives will follow the Prague signing. Leaders from more than 40 countries will gather in Washington next week to discuss improvements in securing nuclear materials.
The White House plans to lead calls for disarmament in May at the United Nations during an international conference on strengthening the Nuclear Non-Proliferation Treaty.
The treaty signed Thursday is the most significant nuclear disarmament pact in a generation, and Medvedev has lauded it as "an important step" in disarmament and arms control efforts.
U.N. Secretary-General Ban Ki-moon welcomed the signing of the New START Treaty as a "milestone in the international efforts to advance nuclear disarmament and to achieve a world free of nuclear weapons," U.N. associate spokesman Farhan Haq said.
Russian analysts say Russia needs the deal to ease the burden of replacing a large number of aging Soviet-built missiles. "This treaty is in Russia's best interests," said Sergei Rogov, the head of the USA and Canada Institute, an influential think tank.
Inside the hall, the anticipated moment came as the two presidents picked up their pens, glanced at each other and grinned as they signed several documents, with aides transferring the papers back and forth so all would have both signatures. When it was done, the leaders seemed momentarily at a loss, with Medvedev flashing a smile and a shrug before they stood to shake hands.
While the Russian parliament is likely to follow the Kremlin's lead, the ratification process in the U.S. Senate could be troublesome. Fearing potential trouble, Moscow has said that Russian lawmakers will synchronize their moves to ratify the deal with the U.S. legislators.
Sensitive to East European concerns, Obama is tending to other business while in Prague — hosting a dinner for leaders from 11 Central and Eastern European nations formerly in or near Moscow's orbit, who worry about the Kremlin's post-communist push for influence.
Under Obama, Russian cooperation on key priorities, from helping to prevent a nuclear-armed Iran to opening supply routes for the U.S. military into Afghanistan and agreeing to new arms reductions, has increased — though not by a huge amount.