The ability to inhibit the function of oncogenes has emerged as a major new paradigm for treating cancer. Although these therapies offer precision with a high probability of clinical benefit the development of resistance is a major issue that is preventing long term disease control in many patients. Two broad approaches are being taken to circumvent this problem. First a systematic study of the mechanisms of resistance that allows rationale development of therapeutic approaches to prevent or overcome resistance. Second the use of alternate therapeutic strategies in combination or in sequence to negate the effects of resistance mechanisms. The disease of melanoma is seeing these strategies splay out to improve outcomes for patients with BRAF-mutant melanoma. The finding of reactivation of MEK and ERK signaling as a major mechanism of resistance to BRAF inhibitors has seen the addition of MEK-inhibitor to a type-I BRAF inhibitor resulting in greater inhibition of MAPK-signaling and improved partial and complete response rates, and prolongation of progression free and overall survival without increasing toxicity in normal cells. Three phase 3 clinical trials have shown highly consistent clinical outcomes defining the combination of a BRAF and MEK-inhibitor as a new standard of care for advanced BRAFV600-mutant melanoma. However resistance to the combination therapy still occurs in the vast majority of patients. Genomic analyses of tumor tissue from patients progressing on combined BRAF and MEK-inhibition suggest reactivation of the MAPK-signaling as one mechanism of resistance. One strategy to overcome this is to inhibit MAPK-signaling downstream at key signaling nodes such as the cell cycle regulator CDK4. Our preclinical studies show that adding a CDK4-inhibitor to a BRAF inhibitor will prevent the emergence of resistance. An alternative strategy is to combine BRAF-inhibitors with therapies that target other mechanisms of disease control such as the host response or tumor metabolism. It is clear that therapeutic combinations either sequentially or concurrently, will continue to define new standards of care for patients with advanced BRAF-mutant melanoma.