The p110 delta isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110 delta-deficient CD8(+) T cells, we demonstrated a critical role for the p110 delta subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110 delta signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110 delta signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110 delta in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110 delta signaling in in vivo CD8(+) T cell immunity to microbial pathogens.