The Ras/Raf/MEK/ERK (or MAPK) signalling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses such as proliferation, growth, differentiation and apoptosis. Perturbation of these processes by aberrant MAPK signalling often leads to malignant transformation as indicated by the frequent occurrence in human cancers of genetic alterations affecting this pathway. In recent years, genetically modified mouse models have proven instrumental in unravelling how deregulated MAPK signalling leads to disease. Indeed, conditional activation of oncogenic K-Ras or B-Raf in mice resulted in neoplasms that closely resemble the human disease. Such tractable mouse models will enable the pursuit of basic biological mechanisms and translational applications regarding the MAPK pathway.