The combination of a greater understanding of the redundant and non-redundant functions of PI3K signaling in T-cells, the systemic toxicities of targeting different isoforms, and the broad availability of isoform selective agents, has initiated a new wave of clinical testing, particularly with using PI3K-α inhibitors for PIK3CA mutated cancers (245, 246), PI3K-β in cancers with PTEN loss (247, 248), and PI3K-δ and -γ inhibitors as cancer immunotherapies and T-cell immunomodulators. The gene discussed is PIK3CD; the disease is cancer.