Toll-like receptors (TLRs) are key sensors of microbially derived molecules that, upon activation, provide a pathogen-specific inflammatory response, leading to an efficient eradication of microbial pathogens. An important question has been how TLRs can provide signaling diversity when challenged with genotypic and functionally distinct pathogens. Recently, two studies have shown that tumor-necrosis factor receptor-associated factor 3 (TRAF3) is an essential component of the TLR-signaling pathway, being a crucial regulator in the induction of TLR-specific inflammatory responses.