ECs (endothelial cells) in the developing vasculature are heterogeneous in morphology, function and gene expression. Inter-endothelial signalling via Dll4 (Delta-like 4) and Notch has recently emerged as a key regulator of endothelial heterogeneity, controlling arterial cell specification and tip versus stalk cell selection. During sprouting angiogenesis, tip cell formation is the default response to VEGF (vascular endothelial growth factor), whereas the stalk cell phenotype is acquired through Dll4/Notch-mediated lateral inhibition. Precisely how Notch signalling represses stalk cells from becoming tip cells remains unclear. Multiple components of the VEGFR (VEGF receptor) system are regulated by Notch, suggesting that quantitative differences in protein expression between adjacent ECs may provide key features in the formation of a functional vasculature. Computational modelling of this selection process in iterations, with experimental observation and validation greatly facilitates our understanding of the integrated processes at the systems level. We anticipate that the study of mosaic vascular beds of genetically modified ECs in dynamic interactions with wild-type ECs will provide a powerful tool for the investigation of the molecular control and cellular mechanisms of EC specification.