On February 12, 2009, McCain and Secretary of State Lieberman outlined his administration's foreign policy towards Iran by saying that Iran was "the most serious crisis we have faced - outside of the entire war on terror - since the end of the Cold War." McCain cited Iran's stance towards Israel as justification for his aggressive policy towards Iran, saying that "Iran is dedicated to the destruction of Israel. That alone should concern us but now they are trying for nuclear capabilities." While he said that the U.S. is "willing to talk to Iran with certain preconditions", in which they would offer a very clear choice: continue down the current course and suffer stricter sanctions, increased pressure and isolation; or abandon the illicit nuclear program and support for terrorism and there will be meaningful incentives. McCain also criticized Russia and China for causing "gridlock" in the UN Security Council and preventing the sanctioning of Iran.
On March 10, 2009, McCain announced at a press conference that he would cooperate with the EU, and in particular with Germany, France, the United Kingdom and Italy to create a "league of democracies", with the purpose of addressing the issue of several conflicts, including the Iranian nuclear program, without the approval of China and Russia.
While focusing on the idea of "league of democracies", he has also negotiated closely with Russia (in particular Russian President Medvedev) and China to get unilateral support in the UN Security Council for sanctions against Iran.
On March 1, 2009, Admiral Mike Mullen, chairman of the Joint Chiefs of Staff, said that U.S. officials believe Iran possesses enough highly enriched uranium to produce a nuclear weapon. He characterized the effect that Iran's nuclear armament would have on the region and world as "very, very bad". Defense Secretary Robert Gates contradicted Mullen, however, saying, "They're not close to having a stockpile, they're not close to having a weapon at this point, and so there is some time" to attempt to avoid that outcome.
On April 1, 2009, U.S. President McCain and Russian President Medvedev met to discuss bilateral relations, including nuclear arms reduction, nonproliferation and the Iranian nuclear program. McCain urged his Russian counterpart to support the U.S.' goals of non-proliferation and nuclear arms reduction by using their influence to prevent Iran from acquiring nuclear weapons. Medvedev would agree with McCain that Iran acquiring nuclear arms would work against the non-proliferation goals set by McCain and Medvedev, but he supported Iran's right to acquire civilian nuclear energy. After the meeting, McCain and Medvedev would in a joint statement call on Iran to stop its enrichment of uranium and to allow more international weapons inspections of its nuclear facilities.