NO is a key transducer of a vasodilator message from the endothelium to vascular smooth muscle. Recently, its actions as a negative inotrope in cardiac muscle have been discovered. In the vasculature, it is synthesized under physiological conditions following activation of a low-output, Ca(2+)-dependent NO synthase (NOS) in endothelial cells. Immune activation triggers the expression of a high-output, Ca(2+)-independent NOS in the vasculature and myocardium, causing the overproduction of NO and significant cardiovascular dysfunction. In this article, Richard Schultz and Chris Triggle briefly review recent findings concerning the role of NO, and other endothelium-derived factors, in vascular smooth muscle function and consider the consequences of its production in the heart.