Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identifying the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. Here, we examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double transgenic Nestin-GFP/NG2-DsRed mice, we had identified two pericyte subsets. In this work, we found that Nestin-GFP-/NG2-DsRed+ (type-1) and Nestin-GFP+/NG2-DsRed+ (type-2) attach to the walls of small and large blood vessels in vivo, and in vitro, type-2, but not type-1, spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 were recruited during its angiogenesis. As inhibiting angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses.