Melanoma has traditionally been associated with limited treatment options, and as such, biomarkers such as histopathologic staging and serum lactate dehydrogenase focused on prognosis. The development of effective treatment options shifted the search to biomarkers for predicting response and resistance to therapy, an arguably more critical goal. Specific genetic alterations (e.g., and mutations) predict response to molecularly targeted agents and are routinely used in clinical practice. Other promising biomarkers include T-cell characteristics (the circulating and tumor microenvironment), tumor expression of PD-L1, circulating DNA, circulating tumor cells and miRNAs. In this article, we discuss the status of the currently used and experimental tumor- and blood-based biomarkers for melanoma prognosis and response to targeted and immune therapies.