The one-year overall survival for patients with metastatic melanoma has risen from 30-35% after treatment with chemotherapy, to >80% for combined targeted or immune therapy. These classes of drugs have different patterns of response and resistance: almost all patients respond to MAPK targeted therapy initially and quickly, however the majority of patients eventually progress. In contrast, 30-40% of patients have no benefit with PD-1 inhibition, and for those that do have marked tumour reduction initially, the median duration of response is nearly 2 years. Translational studies suggest we may improve responses and survival with these drugs using across-class combinations of therapies, including other treatment modalities. Whether drugs and therapies are sequenced or concurrent for optimal outcome is unknown. Addition of other inhibitors or agonists of known or new targets within the melanoma cell or microenvironment may enhance responses and delay resistance. Clinical and translational work examining aspects of treatment-related melanoma biology will be presented, including evaluation of human melanoma tissue at response and at resistance.