Over the past decade the treatment of advanced melanoma has been revolutionized by the approval of new therapeutic agents, including BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (Mitogen-activated protein kinase) inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death protein 1 (PD-1) blocking antibodies, as well as a modified oncolytic herpes virus that is given intratumourally. These changes in the treatment landscape have dramatically improved objective response rates, progression-free survival and overall survival for patients. Specifically, the overall survival of patients with metastatic melanoma has improved from 9 months before 2011 to ongoing longterm tumour control in a subset of patients. However, despite the major advances that have been achieved, the management of advanced melanoma remains challenging as responses to treatment are heterogeneous and not always durable. Hence, additional improvements are clearly required, and several strategies are in clinical development with novel agents in the pipeline. Various combination strategies, combining different immunotherapies with one another (e.g., anti-Lymphocyte-activation gene 3 [LAG-3], pegylated Interleukin-2 [IL-2], Toll-like receptor 9 [TLR-9] agonists, anti-glucocorticoid-induced TNFR-related protein [GITR]) as well as with others (e.g., BRAF/MEK inhibition, intralesional drugs, Histone deacetylases [HDAC] inhibitor, vaccines), mostly in combination with a PD-1 backbone, are being investigated with promising results. Alternative sequencing strategies are also under investigation.