Mitochondrial DNA (mtDNA) is essential for aerobic energy production in eukaryotic cells, and mutations in this genome can lead to mitochondrial dysfunction. Human mtDNA mutations are typically heteroplasmic, a mix of mutant and wild-type genomes, which can present as a heterogeneous group of disorders ranging in severity from mild to fatal, and commonly affecting highly aerobic tissues such as heart, skeletal muscle, and neurons. During the 1990s, many research groups started to notice that mtDNA mutations could segregate depending upon the mutation and tissue. This segregation pattern can have a direct effect on the onset and severity of these mutations. However, these segregation patterns could not be easily explained by respiratory chain function, implying that there is regulation of mtDNA independent of its bioenergetic role. A lot of research on this topic has been largely descriptive, but over the last several years advances in mitochondrial biology have provided some mechanistic insight into the regulation of the organelle and its genome. This review addresses these advances with respect to somatic segregation of mtDNA in mammals.