Genetic polymorphisms, in concert with well-characterized etiology and progression of major pathologies, plays a significant role in aberrant processes afflicting human populations. Mitochondrial heteroplasmy represents a dynamically determined co-expression of inherited polymorphisms and somatic pathology in varying ratios within individual mitochondrial DNA (mtDNA) genomes with repetitive patterns of tissue specificity. The ratios of the MtDNA genomes represent a balance between healthy and pathological cellular outcomes. Mechanistically, cardiomyopathies have profound alterations of normative mitochondrial function. Certain allele imbalances in the nuclear mitochondrial genome are associated with key energy mitochondrial proteins. Mitochondrial heteroplasmy may manifest itself at critical protein expression points, e.g., cytochrome c oxidase (COX). Pathological mtDNA mutations also are associated with the development of congestive heart failure. Interestingly, mitochondrial 'normal vs. abnormal' ratios of various heteroplasmic populations may occur in families. In the translational context of human health and disease, we discuss the need for determining critical foci to probe multiple biological roles of mitochondrial heteroplasmy in cardiomyopathy.