The confrontation over the nuclear question finally came to a head during the administration of George W. Bush. Revelations about Iran's illicit nuclear activities focused the full attention of the international community on the issue for the first time. Six years of on and off negotiations, threats, proposed deals and sanctions resolutions followed, but by the time Bush left office a resolution to the conflict appeared no nearer than it had when he entered it. The failure of the Bush administration to achieve its objective of ending the Iranian nuclear programme was in large part due to the absence of a coherent policy. Initially dominated by hardliners opposed to any form of compromise with Iran, the administration pursued ends that it lacked the means to achieve. Despite subsequently becoming more pragmatic in the face of policy failure, Bush remained unable and/or unwilling to make the changes necessary to construct an effective strategy.

On the Iranian side the exposure of its secret activities meant the regime had to make real choices about the nuclear programme for the first time. What was revealed as a result were deep divisions over what Iran's nuclear goals ought to be and/or what price should be paid to achieve them. From 2003–5 Khatami's government sought to find a compromise with Washington but was rebuffed by the Bush administration. After 2005 Mahmoud Ahmadinejad instigated a policy of no compromise with American demands. The interaction of hardliners on both sides thus ensured the continuation of confrontation and a lack of progress toward a resolution of the nuclear stand-off.

George W. Bush

The incoherence of the second Bush administration's foreign policy- making process was, notoriously, laid bare by the Iraq War. As Deputy-Secretary of State Richard Armitage put it, ‘there was never any policy process… . There was never one from the start.’ It is not surprising to find, therefore, that its Iran policy-making process was no better, and for much the same reasons: deep divisions within the administration over how to deal with Iran and a failure on the part of the president to impose a consistent policy.

Bush's first term State Department was dominated by pragmatic Republican realists who were interested in continuing Clinton's efforts to end US–Iranian conflict through engagement and dialogue.