But the summit has already proved controversial, with Binyamin Netanyahu, the Israeli president, announcing at the last minute he would not be attending after learning that Egypt and Turkey planned to raise the issue of Israel's nuclear arsenal during the talks.
The two countries plan to say Israel must sign up to the 1970 Non-Proliferation Treaty (NPT).
Israel is believed to have an arsenal of between 80 and 200 nuclear warheads, but has never confirmed its existence.
Netanyahu's last-minute decision not to attend the conference comes at a time of strained relations between Israel and the US over disagreement's about Israel's continued building of projects in occupied Jerusalem and the West Bank.
But Hillary Clinton, the US secretary of state, played down the significance of Netanyahu's absence.
"That's a decision for a head of government or head of state. Gordon Brown is not coming from Great Britain. Kevin Rudd is not coming from Australia. King Abdullah is not coming from Saudi Arabia," she said.
Leaders gather in Washington for 'unprecedented' talks on nuclear security
"We have a deep and very close relationship between the United States and Israel that goes back many years. That doesn't mean we're going to agree on everything."
She said a "high-level" Israeli delegation was being sent in place of Netanyahu.
The Washington summit will also require deft diplomacy to avoid tension between India and Pakistan.
The nuclear-armed neighbours resumed talks in February, but Pakistan wants the same civilian nuclear development deal with Washington that India has.
Analysts say it is unlikely that Washington will agree to Pakistan's request due to concerns over security in the country.
But any perceived favouritism towards India could strain the fragile relationship between the South Asian neighbours.