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Epac is an acronym for the exchange proteins activated directly by cyclic AMP, a family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs) that mediate protein kinase A (PKA)-independent signal transduction properties of the second messenger cAMP. Two variants of Epac exist (Epac1 and Epac2), both of which couple cAMP production to the activation of Rap, a small molecular weight GTPase of the Ras family. By activating Rap in an Epac-mediated manner, cAMP influences diverse cellular processes that include integrin-mediated cell adhesion, vascular endothelial cell barrier formation, and cardiac myocyte gap junction formation. Recently, the identification of previously unrecognized physiological processes regulated by Epac has been made possible by the development of Epac-selective cyclic AMP analogues (ESCAs). These cell-permeant analogues of cAMP activate both Epac1 and Epac2, whereas they fail to activate PKA when used at low concentrations. ESCAs such as 8-pCPT-2′-O-Me-cAMP and 8-pMeOPT-2′-O-Me-cAMP are reported to alter Na+, K+, Ca2+ and Cl channel function, intracellular [Ca2+], and Na+–H+ transporter activity in multiple cell types. Moreover, new studies examining the actions of ESCAs on neurons, pancreatic beta cells, pituitary cells and sperm demonstrate a major role for Epac in the stimulation of exocytosis by cAMP. This topical review provides an update concerning novel PKA-independent features of cAMP signal transduction that are likely to be Epac-mediated. Emphasized is the emerging role of Epac in the cAMP-dependent regulation of ion channel function, intracellular Ca2+ signalling, ion transporter activity and exocytosis.