Mitochondrial oxidant damage, including damage to mitochondrial DNA (mtDNA) is a feature of both severe microbial infections and inflammation arising from sterile (non-infectious) sources such as tissue trauma. Damaged mitochondria release intact or oxidized fragments of mtDNA into the cytoplasm, which represent oxidant injury, and the fragments promote a spontaneous innate immune response, exemplifying a modern frontier of immunological research. MtDNA and mitochondrial-derived oxidants are central factors in activating at least three innate immune pathways involving the TLR9 (Toll-like receptor 9), the NLRP3 (NACHT, LRR and PYD domains-containing protein-3) inflammasome, and the cGAS (cyclic AMP-GMP synthase) pathway. The events that allow mtDNA to escape from damaged mitochondria and from damaged cells are incompletely known, but the presence of cytoplasmic mtDNA and cell-free mtDNA as immune regulators are important for understanding the cell's capacity for protecting mitochondrial quality control (MQC) and cell viability during inflammatory states.