The kinase Akt contains two phosphatidylinositol-3 kinase (PI3K)-dependent phosphorylation sites, one in the activation loop (Thr 308 ) and one in the carboxyl-terminal tail (Ser 473 ), both of which are conserved among the members of the AGC kinase family. Under physiological conditions, the phosphorylation of Thr 308 appears to be coordinately regulated with the phosphorylation of Ser 473 . Under experimental conditions, however, the two sites can be uncoupled, suggesting that their phosphorylation is controlled by different kinases and phosphatases. Phosphoinositide-dependent kinase 1 (PDK1), the kinase that phosphorylates the activation loop site, has been unambiguously identified. However, PDK2, a kinase that is hypothesized to phosphorylate the hydrophobic carboxyl-terminal site, remains elusive. This Perspective examines the regulation and biological significance of Akt phosphorylation at Ser 473 . The authors propose that Ser 473 undergoes both autophosphorylation and phosphorylation by other kinases. Both events may be promoted by interactions between PDK1 and phosphorylated or phosphomimetically altered hydrophobic phosphorylation motifs in kinases associated with Akt. These interactions may induce conformational changes in Akt that make Ser 473 accessible to phosphorylation.