The PTEN tumor suppressor is a central negative regulator of the PI3K/AKT signaling cascade that influences multiple cellular functions including cell growth, survival, proliferation and migration in a context-dependent manner. Dysregulation of this signaling pathway contributes to many cancers in man. PTEN is the most commonly altered component of the PI3K pathway in human malignancies. Mutations occur in both heritable and sporadic settings, with high frequency in sporadic glioblastoma, prostate and endometrial cancer. Data from human tumors and animal models support the concept that the effects of PTEN inactivation are tissue-specific. Elucidation of the mechanisms regulating activation of unique downstream effectors that mediate distinct outcomes of PTEN loss will augment our understanding of tumorigenesis and ultimately lead to novel therapeutic options.