Stem cell medicine is gaining momentum in the development of therapy for various end-stage diseases. The search for new seed cells and exploration of their application prospects are topics of interest in stem cell medicine. In recent years, vascular endothelial cells (VECs) have attracted wide attention from scholars. VECs, which form the inner lining of blood vessels, are critically involved in many physiological functions, including permeability, angiogenesis, blood pressure regulation, immunity, and pathological development, such as atherosclerosis and malignant tumors. VECs have significant therapeutic effects and broad application prospects in stem cell medicine for the treatment of various refractory diseases, including atherosclerosis, myocardial infarction, diabetic complications, hypertension, coronavirus disease 2019, and malignant tumors. On the one hand, VECs and their extracellular vesicles can be directly used for the treatment of these diseases. On the other hand, VECs can be used as therapeutic targets for some diseases. However, there are still some obstacles to the use of VECs in stem cell medicine. In this review, advances in the applications and challenges that come with the use of these cells are discussed.