Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was originally cloned as a tumor suppressor for brain tumors. Now it is known as a tumor suppressor for many tumor types. In this review, we ask the simple question: why is PTEN such a common and important tumor suppressor? The most obvious answer is that there are no other family members that can replace PTEN. As a result, several pathways critical for cell transformation are misregulated. The most important of these is the phosphoinositide 3-kinase (P13K) PI3K-Akt pathway, which has downstream effects on transcription, proliferation, cell survival, invasiveness, and angiogenesis. In addition, PTEN is linked via several mechanisms to the p53 tumor suppressor. Through p53 and additional mechanisms, loss of PTEN leads to genomic instability. Hence, PTEN is important because its loss misregulates multiple Akt-dependent and -independent pathways critical for the development of cancer. J. Cell. Biochem. 102: 1368–1374, 2007. © 2007 Wiley-Liss, Inc.