Mitochondria are the cellular organelles which consists of 37 intronless genes that encode 13 subunits of the electron-transfer chain, 2 ribosomal RNAs (rRNA), and 22 transfer RNAs (tRNA). Mutations in mitochondrial DNA (mtDNA) may cause multiple human diseases. Recent researches have shown that reactive oxygen species caused by mitochondria can lead to mtDNA deletion or mutation, mutations of tRNA gene of conserved sequences resulting in defective contractile proteins and oxidative phosphorylation impairment that may increase the myocardial metabolic demands for ATP. Thus, these mitochondrial dysfunctions may contribute to the development of cardiomyopathy. This review summarized the association between mtDNA mutations and cardiomyopathy. These findings provide new insights into the molecular mechanism, management and treatment of cardiomyopathy.