Endothelial cells (ECs) are a multifaceted component of the vascular system with roles in immunity, maintaining tissue-fluid balance, and vascular tone. Dysregulation or dysfunction of ECs can have far-reaching implications, leading pathologies ranging from cardiovascular diseases, like hypertension and atherosclerosis, ischemia, chronic kidney disease, blood-brain barrier integrity, dementia, and tumor metastasis. Recent advancements in regenerative medicine have highlighted the potential of stem cell-derived ECs, particularly from induced-pluripotent stem cells (iPSCs), to treat ischemic tissues, as well as models of vascular integrity. This review will summarize what is known in the generation of ECs with an emphasis on tissue-specific ECs and EC subphenotypes important in development of targeted cell-based therapies for patient treatment.