The importance of apoptosis as a natural means to eliminate unwanted or damaged cells has been realized over the past decade. Many components required to exercise programmed cell death have been identified and shown to pre-exist in most, if not all, cells. Such ubiquity requires that apoptosis be tightly controlled and suggests the propensity of cells to trigger the cellular death machinery can be regulated. Recently, several signaling pathways have been demonstrated to impact the apoptotic potential of cells, most notably the phosphatidylinositol 3′ kinase (PI3′K) pathway. The 3′ phosphorylated lipid products generated by this enzyme promote activation of a protein-serine kinase, PKB/AKT, which is necessary and sufficient to confer cell PI3′K-dependent survival signals. The relevance of this pathway to human cancer was revealed by the recent finding that the product of the PTEN tumor suppressor gene acts to antagonize PI3′K. This review focuses on the regulation and mechanisms by which PKB activation protects cells and the oncologic consequences of dysregulation of the pathway.