Mitochondrial dysfunction is associated with the manifestation and origin of a plethora of diseases and disorders. Whilst classically the role of these archetypical ‘powerhouses’ in many disease phenotypes has been attributed to their ability to regulate cell metabolism and cell death pathways, emerging data posit that mitochondria may also act as powerful initiators and masters of the innate immune response. This new paradigm complements the current mitochondrial dogma, whereby molecules endogenously present on or inside the mitochondria may act as immune regulators in response to stress or pathogens and may also be responsible for the initiation and/or manifestation of chronic inflammation observed in many diseases and disorders.