The general accepted paradigm for cAMP-induced transcription of genes presages that cAMP activates protein kinase A, which in turn phosphorylates the cAMP responsive element-binding protein CREB at the serine-133 residue. Phosphorylated CREB, bound to cAMP responsice element(s) in the promoter of such genes, will subsequently recruit the co-activator CBP or its paralog p300. These co-activators enhance CREB-mediated transcription through linking CREB to the basal RNA polymerase II transcription complex and through their intrinsic acetyltransferase activity, which enables to formation of an open chromatin structure. However, CREB-mediated transcription of cAMP responsive genes remains enigmatic in multiple ways. Despite the ubiquitous expression of protein kinase A, CREB and CBP, many genes display a tissue-specific responsiveness to cAMP. In fact, genes with cAMP responsive element(s) in their promoters can be up-regulated, refractory, or even repressed by increases cAMP levels. This review will discuss several mechanisms that contribute to the outcome of the responsiveness of CREB target gefnes to increases cAMP levels.