Epac1 and Epac2 are cAMP-dependent guanine-nucleotide-exchange factors for the small GTPases Rap1 and Rap2, and are known to be important mediators of cAMP signaling. The recent determination of the crystal structure of Epac2 has indicated a mechanism for the activation of the multi-domain Epac proteins. In addition, these proteins have been implicated in various cellular processes such as integrin-mediated cell adhesion and cell–cell junction formation, the control of insulin secretion and neurotransmitter release. In most of these processes, cAMP signaling through protein kinase A (PKA) is also involved, stressing the interconnectivity between Epac- and PKA-mediated signaling.