The two general mechanisms for altering cardiac contractile state are either a change in cytosolic Ca2+ or a change in the response of the myofilaments to Ca2+. Most endogenous inotropic agents involved in cardiac regulation, e.g., catecholamines, act mainly by altering cytosolic Ca2+. Recent studies indicate that cardiac endothelial cells release diffusible substances that modulate myocardial contraction predominantly through changes in myofilament properties. This mode of action often results in a disproportionate effect on myocardial relaxation and diastolic tone. Myofilament response to Ca2+ is reduced by nitric oxide (acting through elevation of cGMP) and by an unidentified stable low molecular weight substance termed “myofilament desensitizing agent”, with a consequent enhancement of relaxation and reduction in diastolic tone. In contrast, endothelin-1 and angiotensin II increase myofilament response to Ca2+. There appear to be important interactions between these agents and the Frank Starling response, the underlying basis of which is also a change in myofilament response to Ca2+. Under pathological conditions, both the release of endothelial agents and the responses of diseased myocardium to these substances may be altered. A better understanding of the role of this pathway in physiological and pathophysiological states may lead to novel therapeutic strategies.