The Hedgehog (Hh) signaling pathway plays an essential role in embryonic and postnatal vasculature development and homeostasis of organs. Under physiological condition, Hh family’s member Sonic Hedgehog (SHh) regulates endothelial cell growth, promotes cell migration, and induces the construction of blood vessels. In this review, we highlight recent topics in EPC biology, regarding current advance in SHh canonical and non-canonical signaling pathway in EPCs and EC biology in terms of homeostasis, extracellular SHh signal transmission by parental cell-derived extracellular vesicle (exosomes containing single-strand non-codding miRNA), and SHh signal impairment in cardiovascular diseases. Also, we discuss SHh signaling pathway activation of EPCs as a promising therapeutic tool against cardiovascular disease patients.