One of the most studied and best-understood examples of second messenger-regulated gene transcription involves the activation of genes by the cyclic AMP pathway: stimulation of several hormone, growth factor, and neurotransmitter receptors activates adenylyl cyclase, generating cyclic AMP that, by binding to the regulatory subunit of protein kinase A (PKA), dissociates the PKA catalytic subunit. The free catalytic subunit is transported to the nucleus where it phosphorylates and consequently activates the transcription factor CREB. This phosphorylation of CREB allows interaction with the co-activator CBP, which binds to components of the basal transcriptional machinery. CBP and its homologue p300 are targets for several viral-transforming proteins, implying that these co-activators have a more extensive role in cellular function. Indeed, recent studies have demonstrated that multiple transcription factors bind to CBP, including c-jun, c-myb, MyoD, E2F1, YY1, and members of the steroid hormone receptor superfamily, although it is not yet clear which of these transcription factors depend upon CBP for function. Determining exactly which transcriptional pathways require CBP in vivo and which genes are activated by CBP will provide an important clue in developmental regulation and cell cycle control, since mutations in the human CBP gene have been found to cause developmental abnormalities and a predisposition for some types of cancer. In this review, we will discuss the mechanisms involved in the PKA-dependent activation of CREB and describe how the co-activator CBP and its homologue are involved in this process. In addition, we will outline the various transcription factor pathways that CBP has been proposed to activate. Finally, we will discuss the possible role of CBP in cellular transformation and differentiation.