Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been implicated in signal transduction through tyrosine kinase- and heterotrimeric G-protein-linked receptors. We report herein the cloning and characterization of p110δ, a novel class I PI3K. Like p110α and p110β, other class I PI3Ks, p110δ displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras. In contrast to the widely distributed p110α and β, p110δ is exclusively found in leukocytes. In these cells, p110α and δ both associate with the p85α and β adaptor subunits and are similarly recruited to activated signaling complexes after treatment with the cytokines interleukin 3 and 4 and stem cell factor. Thus, these class I PI3Ks appear not to be distinguishable at the level of p85 adaptor selection or recruitment to activated receptor complexes. However, distinct biochemical and structural features of p110δ suggest divergent functional/regulatory capacities for this PI3K. Unlike p110α, p110δ does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity. In addition, the p110δ catalytic domain contains unique potential protein–protein interaction modules such as a Pro-rich region and a basic-region leucine-zipper (bZIP)-like domain. Possible selective functions of p110δ in white blood cells are discussed.