Endothelial cells (ECs) are highly adapted to meet the needs of local tissue and therefore acquire molecular and functional variation according to their location in the body. Although there is little question that the microenvironment of the tissue surrounding the blood vessels significantly influences EC phenotype, very little molecular information exists about vascular endothelium and the degree to which EC expression is modulated within different organs in vivo. Elucidating molecular expression and topography for ECs in multiple tissues constitutes the first step in a systems biology approach to gain a fundamental understanding of functional differences across organ systems and to frame future studies investigating how environmental inputs alter EC gene/protein expression and physiology. This information is vital also for tissue engineering, in which persists a critical lack of understanding of the properties of ECs in the context of normal tissues. By knowing EC expression in a given organ, researchers gain important topographical and functional knowledge, define the set of functional players in each endothelia, and gain key markers both to discover the factors leading to a particular phenotype and maybe to someday re-create the necessary tissue environment in culture. Finally, defining the endothelial proteome in healthy and diseased tissues may reveal further microen-vironmental modulation and may prove clinically useful by identifying new disease biomarkers and, perhaps more importantly, novel targets for site-directed delivery of functional and molecular imaging agents as well as nanomedicines, gene vectors, and drugs.