Epacs (exchange proteins directly activated by cAMP) act as guanine-nucleotide-exchange factors for the Ras-like small G-proteins Rap1 and Rap2, and are now recognized as incontrovertible factors leading to complex and diversified cAMP signalling pathways. Given the critical role of cAMP in the regulation of cardiac function, several studies have investigated the functional role of Epacs in the heart, providing evidence that Epacs modulate intracellular Ca2+ and are involved in several cardiac pathologies such as cardiac hypertrophy and arrhythmia. The present review summarizes recent data on the Epac signalling pathway and its role in cardiac pathophysiology. We also discuss recent advances in the discovery of novel pharmacological modulators of Epacs that were identified by high-throughput screening and their therapeutic potential for the treatment of cardiac disorders.