DNA polymerases are indispensable for maintaining the integrity of the genome, both through faithful replication of DNA and by repairing damage to DNA. Among the 16 highly specialized mammalian polymerases, 15 are involved in maintaining nuclear genetic information. Polymerases R,, δ, and ϵ function in replication and repair of nuclear DNA, and the remaining nuclear DNA polymerases participate in either translesion synthesis to prevent the arrest of nuclear DNA replication, in DNA repair, or in somatic hypermutation, reviewed in refs 1 and 2. In contrast, replication and maintenance of the mitochondrial genome relies on a relatively modest enzyme repertoire. As the only DNA polymerase found in animal cell mitochondria, DNA polymerase γ (pol γ) bears sole responsibility for DNA synthesis in all replication, recombination, and repair transactions involving mitochondrial DNA (mtDNA). Mutations accumulate in mtDNA with age, and mutation of mtDNA has been shown to promote premature aging in mice. Also, mutation and/or depletion of mtDNA has been observed in certain human diseases, and several recent reports link some forms of these diseases to heritable defects in the pol γ gene. This review summarizes the current knowledge of pol γ roles in maintaining mitochondrial DNA, mitochondrial DNA replication and repair, diseases, and aging.