IL-1 receptor-associated kinases (IRAKs) are important mediators in the signal transduction of Toll/IL-1 receptor (TIR) family members. All TIRs with known function are involved in host defense mechanisms, either by the recognition of pathogens or as receptors for proinflammatory cytokines. They play a crucial role in the switch from innate to adaptive immunity in mammals, and the signaling cascades initiated by these receptors are implicated in a number of human diseases. To date, four IRAK genes have been identified in the human genome, namely IRAK1, IRAK2, IRAK-M and IRAK4. Each distinct IRAK may have highly specific downstream target, and therefore, contribute to the specific activation of cellular response upon distinct TLR ligand challenge, such as signaling pathways leading to cellular apoptosis (IRAK2), NF-κB activation and inflammatory cytokine expression (IRAK4 and 2), Stat3 activation and IL-10 expression (IRAK1), and inhibition of NF-κB activation (IRAK-M).