The recruitment of hematopoietic stem cells (HSCs) to the ischemic brain plays a crucial role in functional recovery (Toth et al., 2008; Borlongan, 2011; Borlongan et al., 2011). Notably, Epac1 (exchange protein directly activated by cAMP-1) promotes integrin-mediated cell spreading on and adhesion to laminin-5 (Enserink et al., 2004), and the adhesion of HSCs to endothelial monolayers and to the matrix protein fibronectin (Carmona et al., 2008). Likewise, stimulation of Epac1 in cultured endothelial progenitor cells ex vivo prior to their exogenous intravenous injection promotes their recruitment to and neovascularization in the ischemic limb (Carmona et al., 2008). These raise the intriguing possibility that Epac1 could play a role in HSC recruitment following a stroke. In this study, we found increases in Epac1 in the ischemic brains from humans and rodents. This Epac1 expression was induced by the binding of hypoxia-inducible factor 1α (HIF-1α) to the Epac1 promoter, and was required for the matrix metalloprotease (MMP) mediated recruitment of HSCs. The recruited HSCs contributed to neovascularization, leading to increased blood flow and functional recovery. Importantly, exogenous stimulation or overexpression of Epac1 markedly increased HSC recruitment, and promoted recovery in a rat model of cerebral ischemia.