Mitochondria, the powerhouses inside our cells, were once bacteria. Despite two billion years of evolution, many mitochondrial components retain characteristics akin to their bacterial origin and are potent danger signals if they escape from their mitochondrial barriers. Ordinarily, mitochondria work in tandem with the cell, locked in an armistice, owing to the strong boundaries (two mitochondrial membranes) that maintain the separation between its pro-inflammatory constituents (a.k.a Damage Associated Molecular Patterns; DAMPs) and the rest of the cell. The mitochondria’s own genome (mtDNA), is particularly interesting to our lab since it is a potent DAMP if not properly contained. Indeed, it is becoming increasingly apparent that the release of mtDNA from mitochondria appears to be a common consequence of multiple cellular insults, and the existence of extra-mitochondrial mtDNA (both cytoplasmic or extracellular) has now been linked to a wide variety of pathological conditions. However, the specific mechanism of mtDNA release in each of these settings remains largely unknown, as does the exact contributions of mtDNA to disease aetiology and pathogenesis. Importantly, mtDNA’s immunostimulatory properties provide a tantalising prospect for novel immunotherapies if mtDNA release could be harnessed for therapeutic benefit, though much work remains to assess the viability of such a notion.