Anti-angiogenesis agents and the identification of cancer stem-like cells (CSC) are opening new avenues for targeted cancer therapy. Recent evidence indicates that angiogenesis regulatory pathways and developmental pathways that control CSC fate are intimately connected, and that endothelial cells are a key component of the CSC niche. Numerous anti-angiogenic therapies developed so far target the VEGF pathway. However, VEGF-targeted therapy is hindered by clinical resistance and side effects, and new approaches are needed. One such approach may be direct targeting of tumor endothelial cell fate determination. Interfering with tumor endothelial cells growth and survival could inhibit not only angiogenesis but also the self-replication of CSC, which relies on signals from surrounding endothelial cells in the tumor microenvironment. The Notch pathway is central to controlling cell fate both during angiogenesis and in CSC from several tumors. A number of investigational Notch inhibitors are being developed. Understanding how Notch interacts with other factors that control endothelial cell functions and angiogenesis in cancers could pave the way to innovative therapeutic strategies that simultaneously target angiogenesis and CSC.