Heterogeneity in endothelial cell structure and function among vascular beds has been recognized for decades. However, recent findings have resolved that endothelial cells possess a functional memory based upon where they are in a blood vessel or based upon where they are isolated from within the blood vessel. Functional memory has been identified using integrated in vivo and in vitro bioassays and, most recently, through molecular profiling experiments. Memory is attributed to the epigenetic modification of phenotype that occurs in response to site-specific, cell-environment interaction during vascular development. In the embryo, Notch signal transduction is required for proper large blood vessel formation and function, whereas vascular endothelial cell growth factor (VEGF) is required for many of the processes of early vascular development including vasculogenesis and large vessel formation. Both Notch and VEGF are expressed in the developing lung, and their roles in pulmonary vascular development likely parallel those in the systemic circulation. Thus, integrated molecular profiling and transgenic technology provide new tools to investigate the interplay between epigenetic and environmental modulation of cell phenotype that controls endothelial cell behavior, and will aid in our understanding of the molecular signals required for normal and abnormal lung vascular development and function.