President Barack Obama has said the biggest threat to US security is the possibility of a terrorist organisation obtaining a nuclear weapon.
Speaking on the eve of a nuclear security summit in Washington, he said leaders from 40 states should focus on how to secure nuclear material.
He said groups like al-Qaeda would not hesitate to use nuclear devices.
Neither North Korea nor Iran, two states with disputed nuclear ambitions, have been invited to the summit.
The two countries are viewed by the US as violators of the non-proliferation agreement.
Syria was also left off the invitation list because the US believes Damascus has nuclear ambitions, the Associated Press news agency notes.
But the leaders of nuclear states like India, China and Pakistan are among those coming to Washington for the biggest gathering of world leaders in the US capital in decades, says the BBC's Mark Mardell.
While the issue of what to do about Iran's nuclear ambitions is not on the agenda, it will be at the centre of many discussions, our North America editor adds.
'South African example'
Leaders or other representatives of 47 states are attending the summit.
This is an unprecedented gathering - Mr Obama will hope for an unprecedented outcome
Jonathan Marcus
BBC diplomatic correspondent
Obama's ambitious summit
"The single biggest threat to US security, both short-term, medium-term and long-term, would be the possibility of a terrorist organisation obtaining a nuclear weapon," Mr Obama said.
"This is something that could change the security landscape in this country and around the world for years to come.
"If there was ever a detonation in New York City, or London, or Johannesburg, the ramifications economically, politically and from a security perspective would be devastating."
Mr Obama praised South Africa for being the first country to abandon a nuclear weapons programme.
South Africa had, he said, acquired special standing as a "moral leader" for voluntarily dismantling its nuclear programme in the 1990s,
He thanked its President, Jacob Zuma, for the leadership his government had shown on non-proliferation.
Israel is being represented at the summit only by a deputy prime minister amid reports that its government is worried that Turkey and Egypt might use the occasion to raise the issue of its nuclear arsenal.
Last Thursday, President Obama and Russian President Dmitry Medvedev signed a new Strategic Arms Reduction Treaty reducing each country's deployed nuclear arsenal to 1,550 weapons.
Earlier in the week, Mr Obama approved a new nuclear policy for the United States, saying he planned to cut the nuclear arsenal, refrain from nuclear tests and not use nuclear weapons against countries that did not have them.
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- Prophesy bearer for four religious traditions, revealer of Christ's Sword, revealer of Josephine bearing the Spirit of Christ, revealer of the identity of God, revealer of the Celestial Torah astro-theological code within the Bible. Celestial Torah Christian Theologian, Climax Civilization theorist and activist, Eco-Village Organizer, Master Psychedelic Artist, Inventor of the Next Big Thing in wearable tech, and always your Prophet-At-Large.
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