Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid kinases that phosphorylate phosphatidylinositol 4,5- bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mTOR, and therefore play important roles in cell growth, survival, etc. The phosphatase and tensin homolog deleted in chromosome ten (PTEN), acts as the catalytic antagonist of PI3K by dephosphorylating PIP3 to PIP2. PI3K has become an important drug target for cancer therapy, since gain-of-function mutations of PIK3CA encoding PI3Kα, as well as loss-of-function mutations of PTEN, have been frequently found in human cancers. The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 3 years. While PI3Kβ, &δ and γ isoform-specific PI3K inhibitors (TGX-221, IC87114 and AS-605240) have been developed for therapy of coronary heart disease, asthma, and glomerulonephritis, respectively, a promising PI3Kα specific inhibitor is not yet available. Correspondingly, almost all of the promising PI3K inhibitors under development for caner therapy, such as NVP-BEZ235, GDC-0941 and ZSTK474, are pan-PI3K isoform inhibitors. Each of these pan-PI3K inhibitors seems to induce a common G1 phase arrest. All have shown favorable in vivo anticancer efficacies and low toxicities, and therefore most have entered evaluation in clinical trials. P-Akt and p-S6 have been reported to be feasible pharmacodynamic biomarkers for monitoring the efficacy of these agents. In the process of discovery of these and other PI3K inhibitors, detailed structure-activity relationship studies were carried out. This review summarizes key advances in the development of PI3K inhibitors, which is preceded by an introduction of PI3K family and their functions.