The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis preferentially in cancer cells is attractive for its development as a novel cancer therapeutic agent, but many cancer cell lines are resistant to TRAIL. While the molecular basis for TRAIL resistance is not always clear, a number of factors have been proposed to mediate TRAIL resistance, including decoy receptor, c-FLIP, nuclear factor (NF)-kappaB, and activation of antiapoptotic kinase signaling. Many growth factor receptors mediate their survival signals through the pathway involving recruitment and activation of phosphatidylinositol (PI) 3-kinase and the serine?threonine kinase Akt. The PTEN tumor suppressor is a phosphatase that dephosphorylates the phospholipids phosphorylated by PI-3 kinase, thereby opposing the action of PI 3-kinase, and acts as the primary negative regulator of the PI-3 kinase?Akt pathway in the cell. Loss of PTEN function occurs frequently in human tumors and leads to constitutive activation of Akt in cancer cells. Constitutively active Akt protects cells from TRAIL-induced apoptosis in multiple tumor types. Growth factors such as epidermal growth factor or insulin-like growth factor-1 also inhibit TRAIL-induced apoptosis through the Akt pathway. Akt exerts its antiapoptotic function by its ability to phosphorylate many key components of the cellular apoptotic regulatory circuit, such as BAD, MDM2, FOXO Forkhead transcription factors, and PED?PEA-15 as well as by its role in activating NF-kappaB. Because PTEN loss is common in tumors, strategies to inactivate Akt may be necessary to overcome TRAIL resistance and make TRAIL-based therapy more effective.