Acute heart failure syndromes (AHFS) are a major public health problem and present a therapeutic challenge to clinicians. Commonly used agents in the treatment of AHFS include diuretics, vasodilators (eg, nitroglycerin, nitroprusside, nesiritide), and inotropes (eg, dobutamine, dopamine, milrinone). Patients admitted to hospital with AHFS and low cardiac output state (AHFS/LO) represent a subgroup with very high inhospital and postdischarge mortality rates. Most of these patients require intravenous inotropic therapy. However, the use of current intravenous inotropes has been associated with risk for hypotension, atrial and ventricular arrhythmias, and possibly increased postdischarge mortality, particularly in those with coronary artery disease. Consequently, there is an unmet need for new agents to safely improve cardiac performance (contractility and/or active relaxation) in this patient population. This article reviews a selection of current and investigational agents for the treatment of AHFS, with a main focus on the high-risk patient population with AHFS/LO.