This piece analyses stages of friendly as well as ferocious relationships between United States of America (US) and the Islamic Republic of Iran. The paper identified unhealthy struggle for dominance and the attendant use of surrogates by the countries to achieve their aims. The paper objective centres on ascertaining the causes of the multi-decade sour relations between the states. With the aid of descriptive approach, data obtained from text books, journals, mass media (of international repute), and internet resources were sourced and analysed. Theoretically, Morgenthau’s political realism, with emphasis on interest defined in terms of (political, economic, military and other corollaries) of power was adopted to unravel the relation between the variables. Findings show that US and Iran were allies before a military coup that unseat the democratically elected Prime Minister Mohammed Mossadeq and restored full political powers to the Shah in 1953. There was a trilateral relation amongst Iran, US and Israel; the relationship, necessitated by the fear of Soviet expansion into Middle East by all parties and amplified by Iran’s strategic position between Far-East and Indian Ocean and the need to protect multiple US economic interests in Iran, instilled fears and suspicion among Sunni majority of the region. The paper, also, traces the non-Arab cultural, linguistic, and historic Judeo and Persian national identities distinct in an otherwise predominantly Sunni-Arab region. Also, that a US-Iran war portent the ability to suspend the fragile peace in the Middle East and further wreck the relations between US and host of Iranian super allies. Thus, the paper recommends among others that, there is need for the two sides to maintain their border of influence to allow peace and stability of the international political system though anarchically laden.