Tumor cells carrying driver oncogenes such as mutated BRAF, EGFR and EML4-ALK appear to sustain an oncogene addiction state, in which growth and survival are highly dependent on the continued activity of the oncogenic pathway. The discovery of such dependencies has informed drug development strategies for a variety of cancers. However, patient responses to therapeutic inhibitors of oncogene action are often incomplete and limited by drug resistance. Although genetic factors in resistance are part of the story, emerging evidence suggests that tissue-specific epigenetic mechanisms and reprograming following oncogene inhibition can induce adapted states where there is reduced dependence on the oncogenic activity. These epigenetic states generate heterogeneous sub-populations of drug-tolerant cells that not only limit drug effectiveness, but also constitute a reservoir from which genetically resistant clones are ultimately selected and contribute to disease progression. This represents a major challenge facing development and use of targeted therapies for a variety of cancers. Our research aims at addressing this problem for BRAF-mutant tumors. We are proposing an integrated strategy to dissect the poorly understood epigenetic states at the single-cell level, identify their key regulators, and predict and test efficient ways to block the heterogeneous populations of drug-resistant cells and maximize tumor cell killing. Our findings will help us utilize targeted therapeutics more generally, more precisely, and more effectively to cure cancer.