Innate immunity, the first line of defense against infection, has revealed surprising complexity for what is considered a relatively primitive and conserved function. A diverse array of Toll-like receptors (TLRs) serves to recognize specific components of foreign invaders. Each TLR contains a Toll interleukin-1 receptor (TIR) domain that recruits IL-1R-associated kinases via adaptor molecules. These adaptors induce nuclear translocation of transcription factors like NF-κB or IRF-3, which turn on a variety of cytokines, including IFN-β and IFN-α, and subsequently a large number of interferon-stimulated genes. Most TLRs have been shown to signal through the adaptor protein myeloid differentiation factor 88 (MyD88) or the MyD88 adaptor-like (MAL) protein, but evidence soon suggested that more adaptors were involved in translating the response to pathogens into cytokine production.