In a relatively short period of time, treatment strategies for metastatic melanoma have radically changed leading to an unprecedented improvement in patient survival. In this period, immunotherapy options have evolved from cytokine‑based approaches to antibody‑mediated inhibition of immune checkpoints, cancer vaccines and pharmacological modulation of the melanoma microenvironment. Combination of immunotherapy strategies and the association of immune checkpoint inhibitors (ICIs) with BRAF V600 targeted therapy show encouraging results. The future of drug development in this field is promising. The comprehension of primary and acquired resistance mechanisms to ICIs and the dissection of melanoma immunobiology will be instrumental for the development of new treatment strategies and to improve clinical trial design. Moreover, biomarker discovery will help patient stratification and management during immunotherapy treatment. In this review, we summarize landmark clinical trials of immune checkpoint inhibitors in advanced melanoma and discuss the rational for immunotherapy combinations. Immunotherapy approaches at early stage of clinical development and recent advances in melanoma immunotherapy biomarker development are also discussed.