Heart failure (HF) is a growing global epidemic resulting in significant morbidity and mortality. The pathophysiology of HF with reduced ejection fraction (HFrEF) is characterized by impaired systolic function resulting in diminished cardiac output. A new class of inotropes, cardiac myosin activators were developed to directly augment cardiac sarcomere function and improve myocardial activity in HFrEF. The first drug in this class, omecamtiv mecarbil selectively activates cardiac myosin and improves cardiac contractility by increasing the efficiency of the actin-myosin cross-bridge cycle, increasing the duration of systolic ejection without raising myocardial oxygen demand. The first major trial investigating omecamtiv mecarbil use in HFrEF demonstrated a statistically significant decrease in the composite endpoint of the first HF event or death from cardiovascular causes. A post hoc analysis demonstrated that omecamtiv mecarbil produced a statistically significant reduction in the composite endpoint of time to the first HF event or cardiovascular death among patients with severe HFrEF.