Recent clinical successes in cancer genome-inspired personalized medicine have led to exciting responses, but only a subset of these responses are long-lasting. Tumors are adept at becoming resistant to therapies, and elucidating the molecular mechanisms of cancer drug resistance is critical to pinpointing strategies to prevent these escape routes. We are using both sequencing and functional genomic approaches to develop comprehensive catalogs of drug resistance mechanisms. Examples include using RNAi and ORF/cDNA libraries to identify all genes that induce resistance in cellular models (e.g., Johanesson, et al., Whittaker, et al. ) and integrating these results with the sequencing of resistant samples (e.g., Wagle, et al.). These efforts include analysis of the contribution of the tumor microenvironment to drug resistance.