The phosphoinositide 3-kinases (PI3Ks) have been the focus of a significant body of cancer research since their discovery nearly 40 years ago. These lipid kinases are now known to play central roles in cancer cell proliferation, survival, migration, metabolism, and immunity and serve as the target of numerous investigational and approved therapeutics. One of these kinases, the unique class IB PI3Kγ, which is highly expressed in myeloid lineage cells and myeloid leukemias, plays prominent roles in tumor immune suppression. Inhibition of this kinase has promoted improved antitumor immune responses in recent solid tumor preclinical studies and clinical trials. New studies also identify this kinase as a driver of acute myeloid leukemia self-renewal and as a new target for the treatment of aggressive leukemias.