Geologic evidence indicates that net vertical uplift occurred on a large (kilometer) scale and at accelerating rates during the middle and late Cenozoic in plateaus of southern Asia and the American west. Based on this evidence, General Circulation Model sensitivity tests were run to isolate the unique effects of plateau uplift on climate. The experiments simulated significant climatic changes in many places, some far from the uplifted regions. The basic direction of most of these simulated responses to progressive uplift is borne out by changes found in the geologic record: winter cooling of North America, northern Europe, northern Asia, and the Arctic Ocean; summer drying of the North American west coast, the Eurasian interior, and the Mediterranean; winter drying of the North American northern plains and the interior of Asia; and changes over the North Atlantic Ocean conducive to increased formation of deep water. The modeled changes result from increased orographic diversion of westerly winds, from cyclonic and anticyclonic surface flow induced by summer heating and winter cooling of the uplifted plateaus, and from the intensification of vertical circulation cells in the atmosphere caused by exchanges of mass between the summer-heated (and winter-cooled) plateaus and the mid-latitude oceans. Disagreements between the geologic record and the model simulations in Alaska and the Southern Rockies and plains may be related mainly to the lack of narrow mountain barriers in the model orography. Taken together, the observed regional trends comprise much of the pattern of “late Cenozoic climatic deterioration” in the northern hemisphere that culminated in the Plio-Pleistocene ice ages. The success of the uplift sensitivity experiment in simulating the correct pattern and sign of most of the observed regional climatic trends points to uplift as an important forcing function of late Cenozoic climatic change in the northern hemisphere at time scales longer than orbital variations; however, the modest amplitude of the uplift-induced cooling simulated at high latitudes indicates a probable need for additional climatic forcing.