The use of classic inotropic agents activating the β-receptor-cyclic adenosine monophosphate (cAMP) pathway (ie, dobutamine or milrinone) should be restricted to a “rescue” therapy in patients with acute heart failure and signs of peripheral hypoperfusion (hypotension, renal dysfunction) that is refractory to volume replacement, diuretics, and vasodilators. This approach is largely supported by observations from clinical trials suggesting that both short-term treatment of acute heart failure without an essential requirement of inotropic support as well as long-term inotropic therapy in patients with severe chronic heart failure with classical inotropic agents can increase arrhythmia and mortality. Vice versa, β-receptor blockade, whenever tolerated, improves survival in patients with severe stable heart failure, further supporting the concept that β-receptor stimulation has adverse long-term effects. Positive inotropic therapy stimulating the β-receptor-cAMP pathway should, therefore, be used with caution, given the potential harmful effects. Levosimendan, a novel calcium sensitizer, has recently attracted substantial clinical interest and may be superior to classical inotropes with respect to improving cardiac mechanical efficiency and avoiding adverse effects such as increasing myocardial oxygen uptake or cardiomyocyte death. Earlier clinical studies have suggested a beneficial effect on survival compared with dobutamine or placebo in patients with acute heart failure (LIDO [Levosimendan Infusion vs Dobutamine in Severe Low Output Heart Failure], RUSSLAN [Randomized Study on Safety and Effectiveness of Levosimendan in Patients With Left Ventricular Failure due to an Acute Myocardial Infarction], and CASINO [Calcium Sensitizer or Inotrope or None in Low Output Heart Failure Study] trials). However, more recent data from two large clinical trials (SURVIVE [Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support] and REVIVE [Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of Decompensated Heart Failure] trials) did not confirm these beneficial effects on mortality. Therefore, additional data are required with respect to the optimum dosing of levosimendan and patient selection to reach a definitive conclusion about the role of levosimendan in the management of patients with acute heart failure.