D ominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC^403/+), when treated with calcineurin inhibitors or a K⁺-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca²⁺ concentrations in wild-type cardiac myocytes; αMHC^403/+ myocytes failed to respond. Pretreatment with a Ca²⁺-channel antagonist abrogated diastolic Ca²⁺ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC^403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca²⁺ responses that initiate a hypertrophic response. These data define an important Ca²⁺-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.