Diagnosis of observational and climate model data reveals that the two major U.S. droughts of the 20th Century had distinct causes. Drought severity over the Southern Plains during 1946–1956 is very likely attributable to remote influences of global sea surface temperatures (SSTs). The Southern Plains and adjacent Southwest are regions particularly sensitive to SST variability, and strong La Niña events that occurred during 1946–1956 exposed that region's drought vulnerability. Drought severity over the Northern Plains during 1932–1939 was likely triggered instead by random atmospheric variability. The Northern Plains lies within a region of comparatively low sensitivity to SST variability, and that region's drought exhibited little sensitivity to SST conditions during the Dust Bowl period. Our results indicate that the southern portions of the Great Plains lie within an epicenter of potentially skillful drought predictions for which an ocean observing system is also a vital drought early warning system.