The vertebrate vascular system is comprised of a highly branched network of arteries, capillaries and veins that penetrates all body tissues. To build a functional network during development, endothelial cells must navigate through tissue corridors and precisely project to their targets. Recent results showed that specialized endothelial cells, resembling axonal growth cones, are located at the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor. We have identified several negative regulators of vessel branching, including the Notch ligand Delta-like4 and the UNC5B receptor for the axon guidance cue Netrin-1. Roles for these molecules in vessel morphogenesis during development and in pathological angiogenesis will be described.