Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.