The regulation of angiogenesis, both its increase or decrease, could be an important therapeutic target for a number of diseases. The role of angiogenesis in atherosclerosis and other cardiovascular diseases is currently controversial. Indeed, angiogenic therapy has been widely regarded as an attractive approach to treat ischemic heart disease, but a variety of studies also suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Recent studies have shown that the phosphatidylinositol 3-kinase (PI3K) family of enzymes plays an important role in the regulation of tumor growth and angiogenesis. PI3Ks and their downstream effector PKB/Akt can be activated by a variety of extracellular signals and regulate a number of cellular processes including cell proliferation, survival, protein synthesis, tumor growth and angiogenesis. Several lines of evidence indicate that inhibition of PI3K suppresses angiogenesis and tumor growth. Nonselective PI3K inhibitors, wortmannin and LY294002, are commonly used to inhibit cancer cell proliferation and tumor growth, and sensitize tumor cells to the treatment with chemotherapeutic drugs and radiation. This review will dissect the role of the PI3Ks pathway in different animal models, and will describe possible future directions for the development of novel therapeutic strategies to modulate the angiogenetic process by regulating PI3K signaling.