Endothelial cells display remarkable phenotypic heterogeneity. An important goal is to elucidate the scope and mechanisms of endothelial heterogeneity and to use this information to develop vascular bed-specific therapies. We reexamine our current understanding of the molecular basis of endothelial heterogeneity. We introduce multistability as a new explanatory framework in vascular biology. We draw on the field of nonlinear dynamics to propose a dynamical systems framework for modeling multistability and its derivative properties, including robustness, memory, and plasticity. Our perspective allows for both a conceptual and quantitative description of system-level features of endothelial regulation.