Nitric oxide acts on cardiac muscle mainly via elevation of intracellular cyclic GMP. Exogenous nitric oxide, endogenously-released nitric oxide and cyclic GMP analogues are capable of modifying cardiac muscle contraction in different species and in experimental models as diverse as single isolated myocytes and humans in vivo. Under basal conditions, nitric oxide induces characteristic and relatively selective effects on the relaxation and diastolic phases of the contraction cycle. It abbreviates contraction duration and enhances relaxation in isolated papillary muscles and isolated ejecting hearts. In isolated cardiac myocytes 8-bromo cyclic GMP increases resting diastolic length, as well as abbreviating contraction. The mechanism seems to involve a reduction in myofilament response to calcium. In humans in vivo, both exogenous and endogenously-released nitric oxide enhance LV relaxation and increase diastolic distensibility. Coronary microvascular endothelial cells are in very close proximity to cardiac myocytes and therefore nitric oxide released by such cells could affect myocyte function. The role of myocyte-derived nitric oxide is unknown, but even in isolated myocytes there is an interaction between cyclic GMP and cyclic AMP, with cyclic GMP reducing the positive inotropic response of cardiac muscle to β-adrenergic stimulation. This mechanism also appears to be involved in parasympathetic modulation of cardiac function. The potential physiological and pathophysiological importance of nitric oxide mediated modulation of myocardial contraction is discussed.