It is generally accepted that endothelial progenitor cells (EPCs) can promote postnatal neovascularization and be used for vascular regeneration, thus representing a promising new tool for the treatment of cardiovascular diseases. However, the exact molecular mechanisms and signaling pathways regulating the proliferation, differentiation, and migration of EPCs; their interaction with niche cells; and their regenerative capacity still remain elusive. The Notch signaling pathway shown to be important for the maintenance and differentiation of various stem and progenitor populations is also involved in EPC regulation. In this review, we will summarize the current knowledge about the pivotal role of Notch signaling in EPC biology and EPC-mediated vascular regeneration.