Inotropic agents alter myocardial oxygen consumption by influencing heart rate, by influencing preload and afterload due to vasodilation, and by direct effects on the myocardium. The latter critically depend on the pharmacologic mode of action. Inotropic agents which act by increasing cyclic AMP in the failing human myocardium increase myocardial energy turnover by their effects on excitation-contraction coupling, resulting in a considerable increase in the amount of calcium cycling. Glycosides, which increase contractile force independent of cyclic AMP, increase calcium cycling moderately and do not influence myocardial energy turnover significantly. Calcium-sensitizers, by increasing calcium-affinity of contractile proteins, may increase contractile force and decrease myocardial energy turnover. Peripheral vasodilation following the application of inotropic agents decreases myocardial oxygen consumption due to a decrease in systolic stress-time integral. The energy-saving effect of reduced preload and afterload may counterbalance a direct myocardial energy-wasting effect of some inotropic agents. An increase in heart rate due to inotropic interventions is unfavorable since 1) oxygen consumption increases in proportion to heart rate, and 2) contractile force of the failing human myocardium decreases. The latter was obvious from experimental and clinical studies showing that increasing heart rate increases contractile force and cardiac output in nonfailing human myocardium, but decreases cardiac performance in the failing human heart. In light of the inverse force-frequency relation in failing human myocardium, negative chronotropic drugs may represent a new class of "positive inotropic" agents. Agents reducing heart rate may be beneficial from an energetic point of view by reducing myocardial oxygen consumption and by improving myocardial perfusion due to a prolongation of diastole.