The PI3K pathway constitutes an important pathway for regulating the signaling of multiple essential biological processes for which deregulation might contribute to cancer. As such, the PI3K pathway is one of the most frequently altered pathways in human tumors, providing constitutive pathway activation. The evidence indicates that the PI3K pathway is a potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the pathway at different points. These proteins are kinases, which are very “druggable” targets a priori and, according to the “addiction hypothesis,” cancer cells with this pathway activated will be more dependent upon this pathway for their survival. In this work, we will focus on PI3K protein as a major target for therapeutic intervention. We thoroughly review the clinical achievements and major concerns raised by the pharmacological intervention of PI3Ks.