Abstract
Cancer develops through an evolutionary process driven by mutation and selective pressures imposed by the microenvironment. To be translationally relevant, experimental models must recapitulate these clinical complexities. In this Primer, we consider how different mouse-modeling strategies can be aligned with human tumor evolution, focusing on mutation order, the emergence and competition of initially rare mutant clones within genetically mosaic tissues, and microenvironmental context. By comparing conventional genetically engineered mouse models (GEMMs), transplant-based models, and emerging tools such as somatic editing and the tandem arrayed regulator (TAR) allele system, we offer a guide for selecting the most appropriate mouse model to address specific evolutionary questions.