Arteries are distinguished from veins by differences in gene expression, as well as in their anatomy and physiology. The characterization of arterial- and venous-specific genes may improve our understanding of cardiovascular development and disease. Here we report the results of a subtractive hybridization screen for arterial-specific genes, and describe in detail the expression of a novel arterial-specific gene, Depp (decidual protein induced by progesterone), using a GFP-Cre knock-in that permits a comparison of both instantaneous and cumulative expression patterns in situ. Several features of Depp expression are noteworthy. First, Depp is expressed in endothelial cells of peripheral tissues, but not in atrial or ventricular endocardial cells of the heart. Very few genes have been reported to discriminate between these two cell types, and therefore this specificity may be useful in generating conditional mutations in other genes implicated in cardiovascular development. Second, Depp reveals an unexpected degree of molecular heterogeneity among arterial endothelial cells. Third, Depp is up-regulated in subsets of endothelial cells, in settings of adult neo-vascularization, including tumor angiogenesis. Taken together, these data reveal unanticipated temporal and spatial heterogeneity among arterial endothelial cells of various tissues and organs, raising new questions regarding the functional significance of this diversity.