Enzymatic activities of the proteins encoded in nuclear genome are regulated by transcriptional, translational and post-transcriptional level. Enzymatic activities of proteins encoded in mitochondrial DNA (mtDNA) have been considered to be regulated by the same steps although detailed mechanisms might differ. However, dynamic change of the number of mtDNA, from some hundred to more than ten thousand, should be considered as another novel mechanism to regulate mtDNA-encoded proteins. Recently, we showed the connection of mtDNA depletion and deletion to cancer progression [Higuchi, M., Kudo, T., Suzuki, S., Evans, T.T., Sasaki, R., Wada, Y., Shirakawa, T., Sawyer, J.R., Gotoh, A., 2006. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines. Oncogene 25, 1437-1445]. This review focuses and describes the possible connections of the mitochondrial DNA depletion and deletion to cancer.