1. Familial hypertrophic cardiomyopathy (FHC) is a primary cardiac disorder characterized by myocardial hypertrophy that demonstrates substantial diversity in both genetic causes and clinical manifestations. 2. Clinical heterogeneity can be explained by the causative gene (at least 13 have been identified to date), the position of the amino acid residue affected by a mutation within the protein (over 450 mutations have been reported to date) and modifying genetic and environmental factors. 3. Multiple mutations are found in up to 5% of human FHC cases, who typically present with a more severe phenotype compared with single-mutation carriers (i.e. earlier onset of disease, greater left ventricular hypertrophy and a higher incidence of sudden cardiac death events). 4. Multiple mutations usually involve MYH7, MYBPC3 and, to a lesser extent, TNNI2, reflecting the higher contribution of mutations in these genes to FHC. 5. Multiple-mutation mouse models appear to mimic the human multiple-mutation phenotype and, thus, will help improve our understanding of disease pathogenesis. The models provide a tool for future studies of disease mechanisms and signalling pathways in FHC and its sequelae (i.e. heart failure and sudden death), thereby allowing identification of novel targets for potential therapies and disease prevention strategies.