A large number of agents are currently in development for patients with metastatic melanoma. Potent small molecule inhibitors of mutant BRAF and the immunotherapy agent ipilimumab have demonstrated promising clinical activity and will likely change the standard of care in the future. However, only a fraction of patients currently receive durable benefit from immune therapies, and despite initial high response rates, resistance to the small molecule targeted agents eventually develops. Substantial opportunities exist for developing biomarkers that will lead to improved combinations and to choices for therapy after progression on a prior targeted agent. Development of clinically useful predictive biomarkers in tumor or blood has been particularly difficult for the immune therapies, owing to the complexity of interactions between tumor and host that impact on anti-tumor immune responses. In the setting of multiple active agents, and none capable of producing long-lasting benefit in most patients, it will be critical to develop assays to match individual patients with the treatment or treatments most likely to be effective to produce the greatest benefit in the overall population.