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Interleukin-1 (IL-1) and lipopolysaccharide (LPS) induces cellular responses through IL-1 receptor (IL-1R) and Toll-like receptors (TLR). IL-1R-associated kinases (IRAK, IRAK2, and IRAK-M) regulate the activation of NF-kappaB and MAP kinase (MAPK) by IL-1R/TLR. A novel member in the IRAK/Pelle family was recently identified and designated IRAK-4. Overexpression of IRAK-4 activates NF-kB and MAPK pathways. IRAK-4 interacts with and phosphorylates IRAK-1. IRAK-4-deficient animals are completely resistant to the challenge with LPS. Animals and humans lacking IRAK-4 are impaired in their responses to viral and bacterial challenges. Members in IRAK/Pelle family play a central role in IL-1R/TLR mediated inflammatory responses and in innate immunity.