Since EPAC (exchange protein directly activated by cAMP) proteins interact with a plethora of intracellular signaling molecules, EPAC1 and EPAC2 regulate a wide variety of biologic responses and functions. Alterations in the EPAC signalosome have been implicated in the pathophysiology of a number of diseases such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the EPAC signalosome will help to optimize the pharmacological treatment of these diseases. In addition, specific targeting of the EPAC signaling pathway may open new therapeutic strategies in the pharmacological treatment of these diseases.[1]