 Structure-based design targeting the key difference between the cAMP binding sites of EPAC and PKA led to the identification of a cAMP analogue, 8-pCPT-2’-O-Me-cAMP that is capable of selectively activate EPAC1.Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists.A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs), among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1.