cAMP-response-element-binding protein, CREB, is a 43-kDa leucine zipper transcription factor identified and cloned via the study of cAMP-regulated genes. In the last decade, numerous studies have contributed much to our understanding of CREB structure, function, and CREB-mediated transcription. CREB binds to the cAMP-response-element (CRE) as a homodimer formed via the leucine zipper motif present at its C-terminus; its transcriptional activity is regulated by phosphorylation at Ser133, located within the N-terminal transactivation domain. Active, Ser133-phosphorylated CREB effects transcription of CRE-dependent genes via interaction with the 265-kDa co-activator protein CREB-binding-protein, CBP, which bridges the CRE/CREB complex to components of the basal transcriptional apparatus. This mechanism of CREB activation is effected by diverse signals, including those regulating the intracellular levels of cAMP and Ca+2, growth factors, and cellular stress. Accordingly, CREB-mediated transcription regulates diverse cellular responses, including intermediary metabolism, neuronal signaling, cell proliferation, and apoptosis. In addition to the regulation of CREB by phosphorylation, the viral oncoproteins HBV pX and HTLVI Tax regulate CREB transcriptional efficacy by an alternative mechanism, by increasing its DNA-binding affinity for viral and/or cellular CRE sites. In this review I describe key experiments that have defined the mechanism of CREB activation, with primary emphasis on emerging evidence linking CREB to cellular growth and development.