The PI-3 kinase pathway is a major driving force for human cancer. One common way of stimulating the PI-3 kinase pathway occurs through inactivation of the PTEN tumor suppressor. The mechanisms of PTEN inactivation include mutation, epigenetic silencing and post-translational modification. Improved insight into the regulation of PTEN is leading to a richer understanding of the contribution of PTEN and the PI-3 kinase pathway to human tumors. Understanding the pathology of PI-3 kinase signaling in tumors improves knowledge of cancer etiology and provides novel therapeutic targets.