Among many proangiogenic growth factors, angiopoietin-1 (Ang1, or ANGPT1) is unique because it can induce distinctive vascular remodeling through highly organized angiogenesis and tightening of endothelial cell (EC) junctions. These effects are mediated by synchronous activation of both vascular Tie2 and nonvascular integrin signaling, making Ang1 a viable candidate for therapeutic neovascularization and vascular protection. Ang1 helps delay diabetic complications by restoring microvascular function and can maintain the quiescence of some adult stem cells. Interestingly, Ang1 is dispensable for maintaining normal vasculature throughout adulthood, challenging the original concept of its functions in cell survival and stabilization in quiescent vasculature. This review summarizes recent advances in understanding the biomedical implications of Ang1 and discusses its multifaceted roles in vascular diseases, the mechanisms underlying its effects, and potential therapeutic applications.