The intracellular signaling pathways activated upon ligation of the co‐stimulatory receptor CD28 remain relatively ill‐defined, although CD28 ligation does result in the strong association with, and activation of, phosphatidylinositol (PI) 3‐kinase. The downstream effector targets of the CD28‐activated PI 3‐kinase‐dependent signaling pathway remain poorly defined, but recent evidence from other systems has shown that Akt/protein kinase B (PKB) is a major target of PI 3‐kinase and have indicated that a major function of PKB is the regulation of cell survival events. Given the strong coupling of CD28 to PI 3‐kinase and the known protective effects of both CD28 and PI 3‐kinase against apoptosis in different cell models, we investigated the effects of CD28 on PKB activation. We demonstrate that ligation of CD28 by either anti‐CD28 monoclonal antibodies or the natural ligand B7.1, results in the marked activation of PKB in both the leukemic T cell line Jurkat and freshly isolated human peripheral blood‐derived normal T lymphocytes. Our data suggest therefore, that PKB may be an important intracellular signal involved in CD28 signal transduction and demonstrate CD28 coupling to downstream elements of a signaling cascade known to promote cell survival.