The article reviews the mechanism by which protein kinase B (PKB or Akt) is activated and its downstream actions. PKB is activated through recruitment to cellular membranes by phosphoinositide 3-kinases (PI3Ks) and phosphorylation by 3′-phosphoinositide-dependent kinase-1 (PDK1). PI3Ks generate specific inositol lipids, such as PtdIns(3,4)P2 and PtdIns(3,4,5)P3, which are recognized by the PH domain of PKB. Upon activation, PKB translocates from the cytosol to the plasma membrane and is phosphorylated on Thr308 and Ser473 by PDK1. The activation mechanism involves the interaction of PtdIns(3,4,5)P3 or PtdIns(3,4)P3 with the PH domains of PKB and PDK1, exposing the phosphorylation sites and facilitating their phosphorylation. PKB has multiple substrates, including BAD, human caspase-9, forkhead transcription factors, and IκB kinases, which are involved in cell survival, apoptosis, and transcriptional regulation. PKB also plays a role in insulin signal transduction, Raf protein kinase inhibition, endothelial nitric oxide synthase activation, and BRCA1 phosphorylation. The article discusses the possibility that PDK1 may activate other kinases besides PKB and the implications for substrate recognition.The article reviews the mechanism by which protein kinase B (PKB or Akt) is activated and its downstream actions. PKB is activated through recruitment to cellular membranes by phosphoinositide 3-kinases (PI3Ks) and phosphorylation by 3′-phosphoinositide-dependent kinase-1 (PDK1). PI3Ks generate specific inositol lipids, such as PtdIns(3,4)P2 and PtdIns(3,4,5)P3, which are recognized by the PH domain of PKB. Upon activation, PKB translocates from the cytosol to the plasma membrane and is phosphorylated on Thr308 and Ser473 by PDK1. The activation mechanism involves the interaction of PtdIns(3,4,5)P3 or PtdIns(3,4)P3 with the PH domains of PKB and PDK1, exposing the phosphorylation sites and facilitating their phosphorylation. PKB has multiple substrates, including BAD, human caspase-9, forkhead transcription factors, and IκB kinases, which are involved in cell survival, apoptosis, and transcriptional regulation. PKB also plays a role in insulin signal transduction, Raf protein kinase inhibition, endothelial nitric oxide synthase activation, and BRCA1 phosphorylation. The article discusses the possibility that PDK1 may activate other kinases besides PKB and the implications for substrate recognition.