Hypertrophic cardiomyopathy (HCM) is the most common inherited disease of the heart muscle and is characterized by hyperdynamic contraction and impaired relaxation. HCM can be caused by mutations in genes encoding sarcomere proteins, and such mutations may be responsible for increased power output. Green et al. identify the small molecule MYK-461, which reduces sarcomere power output by inhibiting cardiac myosin ATPase. In genetic mouse HCM models, oral administration of MYK-461 reduced cardiac contractility, prevented or ameliorated ventricular hypertrophy and attenuated myocardial disarray and fibrosis.