The introduction of targeted therapies for the treatment of BRAF-mutant melanomas have improved survival rates in a significant proportion of patients. Nonetheless, the emergence of resistance to treatment remains inevitable in most patients. Here, we review known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition in melanoma cells and the potential strategies to overcome these mechanisms. Multiple genetic and non-genetic mechanisms contribute to treatment failure, commonly leading to the reactivation of the MAPK pathway. A variety of resistance mechanisms are enabled by the underlying heterogeneity and plasticity of melanoma cells. Moreover, it has become apparent that resistance to targeted therapy is underpinned by early functional adaptations involving the rewiring of cell states and metabolic pathways. The evidence presented suggest that the use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes. •Review of known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition.•Resistance to targeted therapy is underpinned by early adaptations such as rewiring of cell states and metabolic pathways.•Discussion of potential strategies to overcome these mechanisms.•The use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes.