The majority of genetic mutations associated with hypertrophic cardiomyopathy (HCM) occur in genes encoding sarcomeric proteins, which are expressed only in cardiomyocytes. However, some manifestations of the HCM phenotype, such as myocardial disarray, interstitial fibrosis, mitral valve abnormalities, and microvascular remodeling, indicate the involvement of other cell lineages. The link between sarcomeric gene defects and these 'extended' HCM phenotypes remains elusive. Based on novel insights provided by cardiac developmental biology, we propose that a common lineage ancestry of the diverse HCM phenotypes not involving the cardiomyocyte can be traced to the pluripotent epicardium-derived cells (EPDCs). During cardiac colonization, EPDCs differentiate into interstitial fibroblasts, coronary smooth-muscle cells, and atrioventricular endocardial cushions as mesenchymal cells. We propose that the cross-talk between healthy EPDCs and abnormally contracting cardiomyocytes might account for the diverse manifestations of HCM, by a putative mechanism of mechanotransduction leading to abnormal gene expression and differentiation.