The search for stem/progenitor cells capable of endothelium regeneration during postnatal life has gained substantial interest over the past decades and led to the discovery of a subset of cells with robust endothelial regenerative capacity. These so-called endothelial colony-forming cells (ECFCs) are phenotypically identical to cultured endothelial cells, but exhibit high proliferative potential, capacity for self-regeneration, and in vivo vasculogenesis potential. ECFCs have been isolated from endothelial cells from several tissues and are rare in the peripheral blood circulation. Our understanding of ECFC biology in disease is at an early stage. In pulmonary arterial hypertension, there is evidence for both beneficial and pathological roles of ECFCs. A favorable ECFC response repairs endothelial cell dysfunction and attenuates right ventricular hypertrophy. In situations with sustained endothelial stress or uncontrolled propagation of a reparative response, proliferation of ECFCs contributes to pathological remodeling.