MAP kinase inhibitors, including BRAF and MEK inhibtors, are the first class of small molecule targeted agents to improve the overall survival of patients with metastatic melanoma. Although almost all patients respond, the extent of response, pattern of disease progression and time to progression are variable, and complete responses are rare. Understanding the clinical heterogeneity of response and progression, and molecular mechanisms behind them is critical to improve outcomes further. For example, when is it appropriate to treat with the MAPK inhibitor beyond progression, and will drug-targeting of one diagnosed resistance mechanism help the patient? Results from a large systematic patient screen of melanoma tissue taken before and during MAP kinase inhibitor therapy, as well as at progression will be presented in the context of clinical heterogeneity of response and progression. The implications for systemic therapies and patient outcomes will be discussed.