Patients with metastatic melanoma had few treatment options until 2011, when two drugs—ipilimumab and vemurafenib—were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5–7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.