Drought is the primary abiotic factors negatively affecting agriculture, causing tremendous reductions in yield world-wide. Drought responsive adaptation strategies require complex molecular responses to including hormone signaling and production of osmo-protectants, as well as developmental responses including stomatal closure, changes to leaf morphology, and altered root system architecture. A common strategy to better understand these adaptation mechanisms is to compare plants with differing drought tolerances and has been successful in multiple crop plants including wheat, rice, and maize. To better understand drought adaptation strategies, we compared the cytosolic- and organelle-enriched protein profiles of leaves from two Sorghum bicolor genotypes with differing pre-flowering drought tolerances after 8-weeks of growth under water limitation. In agreement with previous literature findings, we observed significant drought-induced changes in the abundance of multiple heat shock proteins and dehydrins in both genotypes. We also identified unique proteins that might play a role in genotype dependent drought adaptation.