Pharmacotherapy of heart failure is likely to be most efficacious when individually tailored to the prevailing pathophysiological derangements. Their diagnostic definition and understanding of the mechanisms involved affords the greatest opportunity for their correction and retardation of further progression of the syndrome, together with related improvements in quality of life, reduction of morbid cardiovascular events and improvement in prognosis. Four approaches may be identified, each of which allows rational therapeutic intervention. The disordered contractile geometry of the failing ventricle gives rise to increased ventricular wall tension and myocardial hypertrophy. The phenotype change largely responsible for this progression may be retarded, halted, or even reversed by a reduction of the elevated ventricular pressure and volume induced by diuresis and/or systemic vasodilatation. Knowledge of the subcellular changes responsible for electromechanical coupling and subsequent myocardial cell contraction in the various stages of heart failure is still incomplete. Pharmacotherapeutic interventions with positive inotropic agents have not been universally clinically efficacious, though the digitalis glycosides and, more recently, drugs that increase the sensitivity of the contractile proteins to calcium appear to afford further opportunity as they do not increase myocardial energy expenditure. In this regard, reduction in heart rate is a major determinant of myocardial contractile performance. Vascular stiffness and reduced vasodilator capacity are intrinsic accompaniments of congestive heart failure and exert deleterious effects on the heart by increasing preload and afterload and on the regional circulations by reducing blood flow. The mechanisms responsible include increased activity of the sympathoadrenal and renin-angiotensin-aldosterone systems, as well as reduction of endothelium-derived relaxing factor and increased stiffness of the vascular wall due to oedema. These furnish important targets for vasodilator and diuretic therapy and specific interventions to correct endothelial dysfunction. There are marked morphological and functional alterations of skeletal muscle depending on the severity and duration of the heart failure. These changes, together with activity detraining, contribute to reduced exercise capacity, a primary clinical hallmark of the syndrome. Improvement in muscle blood flow by improvement in cardiac pumping function and vasodilatation of the systemic resistance vessels, together with physical training programmes, constitute the most rational therapeutic approach to this fourth feature of the syndrome of congestive heart failure.