Autoimmune and inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and asthma are chronic and often progressive diseases associated with a dysregulated or an overactive immune system, respectively. The causes and the drivers of these diseases remain ill-defined, and they are characterized by complex cellular interactions between multiple inflammatory cells of the innate and adaptive immune system. Targeting signaling molecules that are required for the activation of multiple immune cells may be the more likely route to success in combating these chronic, immune cell-mediated diseases. This review highlights two such signaling molecules, the related lipid kinases, class I PI3K (phosphoinositide 3-kinase) δ and γ, both of which are primarily expressed in leukocytes and seem to play important roles in their function and activation. It compares and contrasts these two kinases as targets for autoimmune and inflammatory diseases and summarizes efforts toward the development of small molecule inhibitors of PI3Kδ and PI3Kγ.