Poor vascular homeostasis drives many clinical disorders including diabetes, arthritis, atherosclerosis, and peripheral artery disease. Local tissue ischemia resultant of insufficient blood flow is a potent stimulus for recruitment of endothelial progenitor cells (EPCs). This mobilization and homing is a multi-step process involving EPC detachment from their steady state bone marrow niches, entry into circulation, rolling along vessel endothelium, transmigration, and adhesion to denuded extracellular matrix (ECM) where they may participate in neovessel formation. However, these events are often interrupted in pathological conditions partly due to an imbalance in factor presentation at the tissue level. EPC number and function is impaired in patients with vascular diseases and this dysfunction has been proposed as a prominent contributor to disease pathogenesis. Research approaches aimed at providing therapeutic angiogenesis commonly involve the delivery of proangiogenic cells and/or soluble factors. Nevertheless, greater understanding of the mechanisms involved in EPC homing in both healthy and diseased states is critical for improving efficacy of such strategies. This review underscores the matrix-related signals necessary for enhancing EPC recruitment to ischemic tissue and provides an overview of the development of synthetic ECMs that aim to mimic functions of the local native microenvironment for use in therapeutic angiogenesis.