Endothelial cells have an important protective role in maintaining the normal physiologic function of the vascular wall. When these cells become dysfunctional, they lose this protective influence and they actively promote pathophysiological changes within the blood vessel. This review will discuss some of the extracellular signaling mechanisms employed by normal endothelial cells to exert a protective influence in the vascular wall and those signals generated by dysfunctional cells to promote the atherosclerotic process. It will also discuss the intracellular processes that regulate the release/expression of these signals and that control the transformation of this protective cell to one that promotes the development of vascular disease.