As a parasite with a potentially decades-long intracellular stage, Trypanosoma cruzi could represent a case study for extreme mechanisms for the maintenance of mitochondrial sequence integrity. While an intact mitochondrial repertoire of membrane-associated cytochromes and NADH dehydrogenases are required for passage through the insect forms, within the vertebrate host many of these products may be dispensable, as in vertebrate-exclusive relatives. The degeneration seen in maxicircle genomes from clinical isolates and from culture indicates that the maintenance of intact maxicircles and a complete library of minicircles is an uphill battle that the parasite manages actively. Both the maxicircle and minicircle have been implicated in the clinical manifestation of Chagas disease. The implications of both these scenarios on the biology of the parasite relative to the host are discussed.