Genetically engineered mouse (GEM) models have proven to be a powerful tool to study tumorigenesis. The mouse is the preferred complex organism used in cancer studies due to the high number and versatility of genetic tools available for this species. GEM models can mimic point mutations, gene amplifications, short and large deletions, translocations, etc.; thus, most of the genetic aberrations found in human tumors can be modeled in GEM, making GEM models a very attractive system. Furthermore, recent developments in mouse genetics may facilitate the generation of GEM models with increased mutational complexity, therefore resembling human tumors better. Within this review, we will discuss the different possibilities of modeling tumorigenesis using GEM and the future developments within the field.