Mouse gene–targeting studies have documented a central role of the p110δ isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110δ-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110δ in BCR signaling. p110δ activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 α/β (GSK3α/β) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110δ catalytic activity. Resting B cells with inactive p110δ fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110δ is also critical for interleukin 4 (IL-4)–induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110δ mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110δ as a drug target in autoimmune diseases in which B cells play a crucial role.