Abstract The housekeeping enzyme xanthine oxidoreductase (XOR) has been studied intensively over the past 100 years, yet the complexity of its in vivo function is still poorly understood. A large body of literature focuses on the different catalytic forms of XOR and their importance in the synthesis of reactive oxygen and reactive nitrogen species, which are involved in many disease processes. More recently, various protective physiological roles of XOR have been recognized. We summarize for the first time that XOR is a component of the innate immune system. Because XOR is involved in multiple features of innate immunity we suggest that it is central to the evolution and function of this ancient defense system. We present evidence suggesting that XOR is a direct downstream target of the evolutionarily conserved Toll-like receptor–NF-κB pathway and discuss that numerous forms of post-translational modification of XOR could provide intrinsic molecular switches that make XOR an ideal component of various fast innate immune responses.