The session comes at a moment of global unease after terror attacks in Belgium and a steady drumbeat of nuclear provocations from North Korea. U.S. officials say preventing ISIS from obtaining nuclear material remains a top priority heading into the gathering.
President Barack Obama will host dignitaries from 56 nations and organizations for the Nuclear Security Summit, including British Prime Minister David Cameron, Canadian Prime Minister Justin Trudeau, French President Francois Hollande, Indian Prime Minister Narendra Modi, Italian Prime Minister Matteo Renzi and Mexican President Enrique Peña Nieto.
He'll convene a trilateral meeting with Japanese Prime Minister Shinzo Abe and South Korean President Park Geun-hye on Thursday morning, seeking to further improve ties between the Asian leaders who have only recently reconciled after being at odds over historic grievances related to World War II.
Obama will sit for talks with President Xi Jinping of China on Thursday afternoon to discuss security, climate and economic issues.
North Korea will factor heavily into Obama's talks with all three Asian leaders as the hermit nation continues its missile tests, even after rounds of tough sanctions.
He'll also check in with some of the leaders from the so-called P5+1 countries who helped broker the Iran nuclear deal last year as the pact takes effect, including France, Italy and Britain.
One country from that group, Russia, declined to send a representative to the meeting this week, a snub organizers deemed "unfortunate." Russia plays an important role in global nuclear security as one of five "nuclear weapon states" designated by a global non-proliferation treaty.
"Russia's decision to not participate at a high level, we believe, is a missed opportunity for Russia above all. They have benefited enormously from cooperation on nuclear security and non-proliferation in the past," said Ben Rhodes, Obama's deputy national security adviser. "Frankly, all they're doing is isolating themselves in not participating as they have in the past."
Obama declined a request to meet formally with Turkey's Prime Minister, Recep Tayyip Erdoğan, though the White House emphasized that they've met often in the last several months. Erdoğan has come under scrutiny for his efforts to stop the flow of foreign fighters transiting through Turkey from Syria. He's also faced criticism from U.S. leaders for his crackdown on journalists, including from Vice President Joe Biden when he visited Istanbul last month.
In Washington, Erdoğan will hold official talks with Biden and is expected to meet informally with Obama on the sidelines of the summit, Press Secretary Josh Earnest said Tuesday.
Belgium and Pakistan are sending top cabinet officials to the nuclear summit rather than the heads of their governments after terror attacks rocked both countries.
This week's meetings mark the fourth Nuclear Security Summit after Obama announced in 2009 he was spearheading an international effort to secure nuclear material. The three previous sessions were held in Washington, Seoul and The Hague.
Leaders plan to meet Thursday and Friday both at the White House and at the Washington Convention Center to discuss ways to reduce the use of highly enriched uranium and combat nuclear smuggling.
Aside from talks on nuclear security, Obama plans to convene a special session focused on ISIS, including bolstering security in urban centers and preventing the terror group from obtaining chemical or radiological weapons. Officials say ISIS hasn't yet obtained those types of material but the possibility remains a threat.
That prospect came into sharper focus last month after investigators probing the Paris terror attacks found video footage of a top Belgian nuclear official in the apartment of a suspected militant. The discovery led to fears ISIS, also know as ISIL, was setting its sights on a nuclear weapon.
"We have seen those reports about targeting nuclear facilities as part of a broader plot, and certainly the video footage is of concern and suggests there is at least some interest by ISIL," said Laura Holgate, the White House senior director for weapons of mass destruction. "But we don't have any indications it was part of a broader plan to acquire nuclear materials, and we don't have any information that a broader plot exists."
The White House said it was aware of 2,000 metric tons of material that could be used in nuclear weapons -- either highly enriched uranium or separated plutonium -- currently present in civilian and nuclear programs around the world.
"We know that terrorists have the intent and the capability to turn these raw materials into a nuclear device if they were to gain access to them," the White House said in a document previewing the summit, noting it was "impossible to quantify" the likelihood of a nuclear terrorist attack.
Such an incident would "create political, economic, social, psychological and environmental havoc around the world, no matter where the attack occurs," the administration said.
Planning for the session began earlier this year, before the terror attacks in Brussels but after the Paris and San Bernardino, California, mass killings.