EPAC1 (RAPGEF3) is a guanine nucleotide exchange factor for the small GTPases Rap1 and Rap2 that is directly activated by cAMP, offering a broader scope of cAMP effects beyond the canonical PKA pathway. Recent work underscores EPAC1's diverse roles in cell-cell adhesion, endothelial barrier function, immune cell trafficking, and metabolic pathways, including a striking demonstration that it enhances brown fat growth and beige adipogenesis. In cardiomyocytes, EPAC1-mediated regulation of intracellular calcium handling influences both contractile performance and arrhythmic risk, suggesting therapeutic relevance in heart failure. Moreover, EPAC1 activation in endothelial cells strengthens adherens junctions through Rap1 signalling, thereby mitigating vascular leakage under inflammatory or ischemic conditions. In pancreatic β-cells, EPAC1 contributes to insulin secretion and cytoprotective signalling, offering a potential target for managing type 2 diabetes. In oncology, its effect is more context-dependent, with EPAC1 activation reinforcing normal adherens junctions in some cases yet facilitating tumour invasion in others, as shown by the suppression of metastatic spread upon EPAC1 inhibition in pancreatic cancer models. The development of highly selective EPAC1 modulators therefore paves the way for novel therapeutic interventions. EPAC1 is comprised of a regulatory region (RR), containing the allosteric cAMP binding site, and a catalytic region (CR), containing the Rap binding (active) site. The CR is comprised of the RAS-exchange motif (REM), the RAS association (RA), and CDC25 homology domain (CDC25HD). When RAP1 binds to EPAC1, the nucleotide binding site on RAP1 becomes deformed, decreasing both GDP and GTP affinity. The significantly higher GTP concentration in the cell favours GTP binding over GDP. The RR of EPAC1 contains Disheveled Egl-10 Plecstrin (DEP) and a single cyclic nucleotide binding domain (cNBD) (Figure ). In the absence of cAMP, EPACs exist in an auto-inhibited state, where the RR is blocking the Rap binding site on the catalytic region. The hinge between the two regions adopts a helical conformation, while the adjacent phosphate binding cassette (PBC) sterically blocks the hinge from moving and revealing the Rap binding site. The coupling of the conformational changes between the PBC and hinge is highlighted in the L273W mutant.