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Through release of paracrine and autocrine substances, the vascular endothelium exerts a profound influence on the contractile and growth state of underlying vascular muscle. In heart failure, there is now compelling evidence that endothelium-mediated relaxation is attenuated in response to muscarinic stimulation in both the coronary and peripheral circulation of humans. This impaired response is present regardless of the etiology of heart failure. The mechanisms, significance and etiologic importance of this endothelial defect are not yet understood. Possibilities include 1) alterations in endothelial cell surface receptors or abnormalities of postreceptor signal transduction; 2) abnormalities of endothelium-derived relaxing factor production or release; 3) rapid inactivation of endothelium-derived relaxing factor; and 4) an increase in endothelium-derived contracting factor production and activity in heart failure. We currently have little understanding of the mechanisms accounting for this dysfunctional state of the endothelium. Future research efforts should be directed toward an understanding of these mechanisms.