Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models.