The mitochondrion provides a coordinating platform to anchor and compartmentalize distinct and interactive protein complexes to sustain basic life functions. These include bioenergetics, reactive oxygen species regulation, autophagy, apoptosis and type 1 interferon innate immune response. A number of mitochondrial proteins that are actively shuttled between the mitochondria and other subcellular compartments have been shown to control key immune signaling pathways, such as NF‑κB and IRFs, in response to PAMPs (Pathogen‑Associated Molecular Patterns). We have previously proposed that these proteins form mitochondrial immune signaling complex(es) (MISC), which mediate(s) a host of immune functions, a primary one being the production of type 1 interferons and inflammatory cytokines. This chapter focuses on the composition and functions of MISC, its regulatory mechanisms, and its association with upstream and downstream signaling molecules.