Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute–sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.