The progression of heart failure is related to local and systemic neuroendocrine activation. On the level of the myocardium, neuroendocrine activation (angiotensin II, endothelin, aldosterone, norepinephrine) as well as mediators of inflammation and free oxygen radicals contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac disease are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca(2+)-exchanger. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression and desensitization of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced basal and catecholamine-stimulated activity of adenylate cyclase and a reduction in intracellular cAMP content. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling mechanism seems to be unaltered in isolated human myocardium from failing hearts. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.