Blood vessels are central to numerous vital processes during development, homeostasis and disease. They arise from complex developmental processes that culminate in the formation of a functional vascular network with a hierarchical organization of tubules with different calibers and shapes. These tubules, or vessels, are structurally distinguished by a particular combination of endothelial cells (ECs), pericytes (PCs) or smooth muscle cells (SMCs). ECs form the inner lining of blood vessels and are the most studied vascular cell type. The Notch cell-to-cell signaling family of transmembrane receptors and ligands are well known to be required for the proper differentiation of cells in a variety of tissues. In recent years, several genetic and pharmacological studies uncovered a critical function of Notch in distinct aspects of the biology of blood vessels. It has also become clear that Notch is modulated by many other signaling systems that are important for blood vessel formation, showing that Notch is indeed an important hub in vascular patterning. In this review we will focus on the role of Notch in endothelial sprouting, a process that has to be properly balanced for functional angiogenesis. We will also discuss and summarize the most recent studies concerning upstream regulators and downstream effectors.