Deregulation of the PI3K pathway is common in human cancer. The basic players in this pathway are the kinases PI3K and AKT and the phosphatase PTEN. This review will summarize some of the key animal models that have helped us understand this signaling network and its contribution to tumorigenesis. Recently, great advances in cancer mouse models have been achieved . While germline deletion often affects the development of the organism and can result in embryonic lethality, conditional knockout mouse models offer the possibility of inducing gene deletion in the adult organism. Another useful strategy involves the inactivation of enzyme function by introducing small mutations in the gene sequence, thereby maintaining the protein in an inactivated state and mimicking protein inhibition with drugs. Combining tissue-specific expression of PI3K and AKT with a secondary oncogenic event, for example, leads to the development of specific tumors. Such models are more accurate for growth studies of human tumors than those involving xenograft tumors, due to the interconnection of the tumors with blood vessels. These studies will improve the pharmacological analysis of drug candidates. With the discovery of oncogenic mutations in members of the PI3K pathway, mouse lines harboring these mutations are being developed in order to imitate the molecular features of a human tumor. Using these models for drug testing may enable more accurate prediction of the effects that a specific drug will have on a patient.