The growing sprout moves along a VEGF gradient. Tip cells adhere to the ECM, mediated by integrins, and migrate toward guidance signal molecules (e.g., semaphorins and ephrins). Stalk cells trail behind the tip cell and proliferate to allow sprout elongation and lumen formation. While Notch signaling inhibits proliferation, expression of Nrarp at branch points allows Wnt signaling to maintain stalk cell proliferation. This system allows vascular migration/directionality (by tip cells) and elongation of the shaft (by proliferating stalk cells). When two tip cells meet, they fuse (anastomose); this mechanism is assisted by macrophages, which accumulate at sites of vascular anastomosis to act as bridge cells by interacting with the neighboring tip cells’ filopodia. Once contact between the tip cells has been established, VE-cadherin–containing junctions further strengthen the connection. Perivascular macrophages further stimulate sprouting by producing angiogenic factors or proteolytically liberating them from the ECM. The stalk cells also deposit BM and recruit pericytes, thus stabilizing the forming vessel. Pericyte precursors are attracted to vessels by EC-expressed PDGF. Once at the vessel, these mesenchymal precursor cells differentiate to pericytes in response to TGF-β and decrease EC migration, proliferation, and vascular leakage, resulting in nascent vessel stabilization. Key molecular players discussed in this Review and elsewhere (5, 132) are indicated.