In 1997, PTEN (phosphatase and tensin homologue deleted on chromosome 10, 10q23.3) was identified as an important tumor suppressor gene that is inactivated in a wide variety of human cancers. Ever since, PTEN's function has been extensively studied, and huge progress has been made in understanding PTEN's role in normal physiology and disease. In this review, we will systematically summarize the important data that have been gained from gene inactivation studies in mice and will put these data into physiological context using a tissue-by-tissue approach. We will cover mice exhibiting complete and constitutive inactivation of Pten as well as a large number of strains in which Pten has been conditionally deleted in specific tissues. We hope to highlight not only the tumor suppressive function of Pten but also its roles in embryogenesis and in the maintenance of the normal physiological functions of many organ systems.