The phosphoinositide 3-kinase (PI3K) pathway is one of the most important signaling cascades in cancer, and PI3K is a well established target for anticancer therapy. Since the discovery of the first two compounds that inhibit PI3K, wortmannin and LY294002, a wealth of PI3K inhibitors of various chemotypes have been identified, and nearly twenty of them are currently in various stages of clinical trials. This review outlines the current landscape of the development of small molecule PI3K inhibitors with a focus on structure–activity relationships (SAR) and discussion of co-crystal structures.