Mitochondrial diseases display great diversity in clinical symptoms and biochemical characteristics. Although mtDNA mutations have been identified in many patients, there are currently no effective treatments. A number of human diseases result from mutations in mtDNA-encoded proteins, a group of proteins that are hydrophobic and have multiple membrane-spanning regions. One method that has great potential for overcoming the pathogenic consequences of these mutations is to place a wild-type copy of the affected gene in the nucleus, and target the expressed protein to the mitochondrion to function in place of the defective protein. Several respiratory chain subunit genes, which are typically mtDNA encoded, are nucleus encoded in the chlorophyte algae Chlamydomonas reinhardtii and Polytomella sp. Analysis of these genes has revealed adaptations that facilitated their expression from the nucleus. The nucleus-encoded proteins exhibited diminished physical constraints for import as compared to their mtDNA-encoded homologues. The hydrophobicity of the nucleus-encoded proteins is diminished in those regions that are not involved in subunit-subunit interactions or that contain amino acids critical for enzymatic reactions of the proteins. In addition, these proteins have unusually large mitochondrial targeting sequences. Information derived from these studies should be applicable toward the development of genetic therapies for human diseases resulting from mutations in mtDNA-encoded polypeptides.