As recently as the early 1990s, Americans living in rural and urban areas voted similarly in presidential elections, yet in the decades since, they have diverged sharply as rural people in all regions of the country have increasingly supported the Republican Party. We seek to explain the sources of this growing cleavage by examining two interrelated processes of change: political-economic transformation that elevated many urban areas and marginalized rural ones, and the nationalization of policy goals. Our analytical approach is developmental, probing the timing and sequencing of trends across more than four decades. It is also comprehensive, testing theories related to economic decline, the educational gap, organizational mobilization, and racism and racial and ethnic threat. Our analysis reveals that while rural and urban counties resembled each other in several respects in the 1970s, they have since moved apart. We examine how key trends relate to political change in presidential voting. We find that in the 1990s and early 2000s, rural dwellers in places experiencing population loss or economic stagnation began to support Republican candidates. Then from 2008 to 2020, those in areas with higher percentages of less-educated residents, a higher presence of evangelical congregations per capita, and higher levels of anti-Black racism, each more prevalent in rural areas than urban areas, shifted their support to Republicans. Through sequential processes of polarization, with political-economic forces leading the way and activating rural resistance to the nationalization of policy goals subsequently, the rural-urban political divide emerged as a major fault line in the nation’s politics.