A cell needs to overcome a number of failsafe mechanisms in order to become cancerous (Hahn and Weinberg, 2002). The cell must evade apoptosis and senescence programs to survive the withdrawal of the proper growth factors and nutrients (Schmitt, 2003); it must override DNA damage checkpoints and continue proliferating to propagate existing mutations and acquire new mutations (Malumbres and Barbacid, 2001); and it must maintain a high growth rate to keep up with the demands of rapid cell division (Ruggero and Pandolfi, 2003). Phosphoinositide 3-kinase (PI3K) is a major signaling component downstream of growth factor receptor tyrosine kinases (RTKs)(Cantley, 2002). PI3K catalyzes the production of the lipid second messenger phosphatidylinositol-3, 4, 5-triphosphate (PIP3) at the cell membrane. PIP3 in turn contributes to the recruitment and activation of a wide range of downstream targets, including the serine-threonine protein kinase Akt (also known as protein kinase B). The PI3K-Akt signaling pathway regulates many normal cellular processes including cell proliferation, survival, growth, and motility—processes that are critical for tumorigenesis. Indeed, The role of this pathway in oncogenesis has been extensively investigated and altered expression or mutation of many components of this pathway have been implicated in human cancer (Vivanco and Sawyers, 2002). Although both growth factor RTKs and G protein-coupled receptors can activate PI3K signaling, the involvement of the latter in cancer is less clear. Here we will limit the scope of our discussion only to the PI3K-Akt pathway downstream of growth factor RTKs. The molecular pathways downstream of PI3K and Akt have been reviewed in detail recently (Cantley, 2002; Vivanco and Sawyers, 2002). Therefore, we below highlight the contribution of this pathway to the development of cancer and focus on the promising approaches toward targeting this pathway for cancer therapeutics.