Heart failure is associated with significant morbidity and mortality despite significant advances in therapies developed for it. Because impaired cardiac contractility plays a central role in systolic HF, drugs increasing cardiac contractility (positive inotropics) have been widely used for HF treatment. Conventional inotropics that increase cAMP and intracellular Ca2+ levels improve symptoms and hemodynamics, but also increase myocardial oxygen demands, cardiac arrhythmias, and mortality, which decreases their overall therapeutic benefit-risk ratio in HF. Thus, we need new inotropic agents with different mechanisms of action that improve clinical outcomes. This review describes the mechanism of action and preliminary clinical results obtained with these new investigational positive inotropic agents.