An accumulating body of experimental data supports the presence of a paracrine pathway for the modulation of myocardial function by cardiac endothelial cells. Cardioactive substances released by endothelial cells include nitric oxide, endothelin-1, prostanoids, adenylpurines, natriuretic peptides, and other agents that have so far only been characterised in bioassay studies. Endothelial cells also possess enzymatic activities, in particular ACE/kininase activity, which can alter local levels of angiotensin II and bradykinin. Many of the “endothelial” mediators can be produced by cardiac myocytes themselves, often under pathological conditions, suggesting a potential parallel autocrine pathway. Complex reciprocal relationships exist between individual mediators, which affect both their release and actions. Most studies to date have focused on the acute influence of these agents on contractile function; the longer-term modulation both of cardiac structure and function could be equally important. A notable feature of the action of several of the endothelial mediators is that they modify myocardial contractile behaviour predominantly through changes in myofilament properties rather than by altering cytosolic Ca2+ transients. This mode of action often results in a disproportionate effect on myocardial relaxation and diastolic tone. The opposing contractile effects and differing time-scales of action of agents such as nitric oxide and endothelin-1 are reminiscent of the interplay between these factors in the regulation of blood vessel tone. The endothelial paracrine pathway is likely to act in concert and to interact with other cardiovascular regulatory pathways, e.g., the Frank-Starling mechanism, neurohumoral influences, the effects of heart rate, coronary perfusion and load. A better understanding of its physiological and pathophysiological roles may lead to novel therapeutic strategies.