The cyclic AMP (cAMP)-binding proteins, Epac, are guanine nucleotide exchange factors for the Ras-like small GTPases. Since their discovery in 1998 and with the development of specific Epac agonists, many data in the literature have illustrated their critical role in multiple cellular events mediated by the second messenger cAMP. Given the importance of cAMP in cardiovascular physiology and physiopathology, there is a growing interest to delineate the role of these multi-domain Epac in the cardiovascular system. This review will focus on recent pharmacological and biochemical studies aiming at understanding the role of Epac in cardiomyocyte signaling and hypertrophy.