A decade of work has indisputably defined PTEN as a pivotal player in human health and disease. Above all, PTEN has been identified as one of the most commonly lost or mutated tumor suppressor genes in human cancers. For this reason, the generation of a multitude of mouse models has been an invaluable strategy to dissect the function and consequences-of-loss of this essential, evolutionary conserved lipid phosphatase in tumor initiation and progression.In this chapter, we will summarize the mouse models that have allowed us to faithfully recapitulate features of human cancers and to highlight the network of connections between the PTEN signaling cascade and other oncogenic or tumor suppressive pathways.Notably, PTEN represents one of the most extensively modeled genes involved in human cancer and exemplifies the strength of genetic mouse modeling as an approach to gain information aimed to improve our understanding of and ability to alleviate human disease.