To better understand the molecular basis of vascular cell system behavior in inflammation, we used gene expression microarrays to analyze the expression of 7,075 genes and their response to IL-1beta and TNFalpha in cultures of coronary artery endothelium and smooth muscle derived from a single coronary artery. The most noticeable difference between the cell types was the considerably greater magnitude and complexity of the transcriptional response in the endothelial cells. Two hundred and nine genes were regulated in the endothelium and only 39 in vascular smooth muscle. Among the 209 regulated genes in the endothelium, 99 have not been previously associated with endothelial cell activation and many implicate the endothelium in unconventional roles. For example, the induced genes include several that have only been associated with leukocyte function (e.g., IL-7 receptor, EBI-3 receptor) and others related to antiviral and antibacterial defense (e.g., oligoadenylate synthetase, LMP7, toll-like receptor 4, complement component 3). In addition, 43 genes likely to participate in signal transduction (eg. IL-18 receptor, STK2 kinase, STAF50, ANP receptor, VIP receptor, RAC3, IFP35) were regulated providing evidence that a major effect of TNFalpha and IL-1beta is to alter the potential of the endothelial cell to respond to various other external stimuli.