The RAS–RAF–MEK–ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway.