The Notch pathway is a versatile regulator of cell fate specification, growth, differentiation, and patterning processes in metazoan organisms. In the vertebrate cardiovascular system, multiple Notch family receptors and several of their Jagged and Delta-like ligands are expressed during critical stages of embryonic and postnatal development. Functional studies in mice, fish, tumor models, and cell culture systems have shown that the angiogenic growth of the blood vessel network, the proliferation of endothelial cells, and the differentiation of arteries and veins are controlled by Notch signaling. Moreover, Notch pathway components play important roles in human pathological conditions involving the vasculature, namely CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and Alagille syndrome. Recent findings highlight the Notch ligand Delta-like 4 as a key regulator of tumor angiogenesis and suggest that this protein might be a promising target for cancer therapy.