The vascular endothelium provides a semi-permeable barrier, which restricts the passage of fluid, macromolecules and cells to the surrounding tissues. Cyclic AMP promotes endothelial barrier function and protects the endothelium against pro-inflammatory mediators. This study analyzed the relative contribution of two cAMP targets, PKA and Epac1, to the control of endothelial barrier function and endothelial cell migration. Real-time recording of transendothelial electrical resistance showed that activation of either PKA or Epac1 with specific cAMP analogues increases endothelial barrier function and promotes endothelial cell migration. In addition, reduction of Epac1 expression showed that Epac1 and PKA control endothelial integrity and cell motility by two independent and complementary signaling pathways. We demonstrate that integrin-mediated adhesion is required for PKA, but not Epac1-Rap1-driven stimulation of endothelial barrier function. In contrast, both PKA- and Epac1-stimulated endothelial cell migration requires integrin function. These data show that activation of Epac1 and PKA by cAMP results in the stimulation of two parallel, independent signaling pathways that positively regulate endothelial integrity and cell migration, which is important for recovery after endothelial damage and for restoration of compromised endothelial barrier function.