Historian James A. Bill famously described America’s relationship with Iran as a tragedy. “Few international relationships,” he wrote, “have had a more positive beginning than that which characterized Iranian-American contacts for more than a century.” The nations’ first diplomatic dealings in the 1850s resulted in a treaty of friendship, and although the U.S. government remained largely aloof from Iranian affairs until World War II, many Iranians saw Americans and the United States positively by the early 20th century. The United States became more deeply involved with Iran during the Second World War, and the two nations were close allies during the Cold War. Yet they became enemies following the 1979 Iranian Revolution. How did this happen? The events that led to the Islamic Republic of Iran dubbing the United States the “Great Satan” in 1979 do indeed contain elements of tragedy. By the late 19th century, Iran—known to Americans as “Persia” until the 1930s—was caught in the middle of the imperial “Great Game” between Great Britain and Russia. Although no European power formally colonized Iran, Britain and Russia developed “spheres of influence” in the country and meddled constantly in Iran’s affairs. As Iranians struggled to create a modern, independent nation-state, they looked to disinterested third parties for help in their struggle to break free from British and Russian control. Consequently, many Iranians came to see the United States as a desirable ally. Activities of individual Americans in Iran from the mid-19th century onward, ranging from Presbyterian missionaries who built hospitals and schools to economic experts who advised Iran’s government, as well as the United States’ own revolutionary and democratic history, fostered a positive view of the United States among Iranians. The two world wars drew the United States into more active involvement in the Middle East, and following both conflicts, the U.S. government defended Iran’s sovereignty against British and Soviet manipulation. The event that caused the United States to lose the admiration of many Iranians occurred in 1953, when the U.S. Central Intelligence Agency and the British Secret Intelligence Service staged a coup, which overthrew Iran’s democratically elected prime minister, Mohammad Mossadegh, because he nationalized Iran’s oil industry. The coup allowed Iran’s shah, Mohammad Reza Shah Pahlavi, to transform himself from a constitutional monarch into an absolute ruler. The 1953 coup, coupled with the subsequent decades of U.S. support for the Shah’s politically repressive regime, resulted in anti-American resentment that burst forth during the 1979 Iranian Revolution. The two nations have been enemies ever since. This article traces the origins and evolution of the U.S. relationship with Iran from the 19th through the early 21st centuries.