Defects in heme biosynthesis have been associated with a large number of diseases, but mostly recognized in porphyrias, which are neurovisceral or cutaneous disorders caused by the accumulation of biosynthetic intermediates. However, defects in the maturation of heme groups that are part of the oxidative phosphorylation system are now also recognized as important causes of disease. The electron transport chain contains heme groups of the types a, b and c, all of which are directly involved in electron transfer reactions. In this article, we review the effect of mutations in enzymes involved in the maturation of heme a (the prosthetic group of cytochrome c oxidase) and heme c (the prosthetic group of cytochrome c) both in yeast and in humans. COX10 and COX15 are two genes, initially identified in Saccharomyces cerevisiae that have been found to cause infantile cytochrome c oxidase deficiency in humans. They participate in the farnesylation and hydroxylation of heme b, steps that are necessary for the formation of heme a, the prosthetic group required for cytochrome oxidase assembly and activity. Deletion of the cytochrome c heme lyase gene in a single allele has also been associated with a human disease, known as Microphthalmia with Linear Skin defects (MLS) syndrome. The cytochrome c heme lyase is necessary to covalently attach the heme group to the apocytochrome c polypeptide. The production of mouse models recapitulating these diseases is providing novel information on the pathogenesis of clinical syndromes.