The developing vascular system is regulated by a series of intrinsic and extrinsic signaling interactions that result in the formation and specialization of vessels that circulate blood and lymph around the body. Signaling molecules, such as vascular epithelial growth factors (VEGFs) and angiopoietins, that establish the cellular identity of the endothelial cells in the early embryo also play roles in establishing whether developing vessels will be arterial, venous or lymphatic. Genetic studies in zebrafish and mice have suggested a key role for Notch signaling, downstream of VEGF-A, in specifying arterial versus venous fate, and for VEGF-C and -D, along with the transcription factor, Prox1, in specifying lymphatic fate.