The serine threonine kinases BRAF and MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] are major regulators of the ERK/MAPK pathway, which is deregulated in the majority of melanomas. Targeting BRAF is an effective therapy for advanced melanoma, but patients progress due to the development of resistance. This 'acquired resistance' is thought to be based on a minority of tumour cell populations that are resistant and will eventually re-establish tumour growth even in the presence of drug. In particular, mutations, amplifications or overexpression of genes encoding regulators of the MAPK pathway can confer this resistance, because it allows the melanoma cells to bypass inhibitor action by stimulating ERK activation through alternative routes. Furthermore, there are mechanisms that produce resistance by enhancing the tolerance of melanoma cells to the cytotoxic effects of the drug. These compensatory mechanisms can activate survival signals in the melanoma cells without reactivating ERK. Besides these cell-autonomous resistance mechanisms, stromal fibroblasts in the tumour microenvironment have been identified as a potential source of resistance, because these cells can produce growth factors that reactivate ERK through paracrine signalling. Understanding and further identifying mechanisms of resistance is crucial for the future treatment of advanced melanoma, because this can inform the design of improved therapies with more durable responses.