Over the past four decades, the relationship between Iran and the US has been marked by conflicts, ranging from hostage-taking and sanctions to military confrontation. The present research aims at explaining the dispute by referring to the mindsets of the two countries’ leaders and exploring their epistemological origins. The main question this article seeks to answer is: what are the roots of disputes in US–Iran relationship in the post-Revolutionary era? The hypothesis is that the US governments’ materialistic and Iranian leadership’s idealist, ideational and identity-oriented approaches have led to diverging perceptions on different issues at stake. This has precluded a common understanding between the leaderships of the two countries.