Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder causing heart failure and rhythm abnormality and death. To understand the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a mutation (Arg663His) in the myosin heavy chain gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and abnormal rhythm. Calcium imaging indicated dysregulation of calcium cycling and elevation in intracellular calcium as central mechanisms for disease pathogenesis. Pharmacological restoration of calcium homeostasis prevented development of heart muscle cell enlargement and irregular electrical properties. We anticipate that these findings will help elucidate the mechanisms underlying HCM development in patients and identify novel therapies for the disease.