Toll-like receptors (TLRs), interleukin 1 receptor (IL-1R), IL-18 receptor (IL-18R) and plant R are vital to the induction of acute inflammation as well as various adaptive immune responses upon invasion of microorganisms. These receptors share a common cytoplasmic domain called the TIR (TLR / IL-1R / plant R) domain and the signaling cascade involving the TIR domain is conserved from invertebrate to vertebrate. The engagement of TIR domain containing receptors initiates their signaling through several intermediate proteins including serine-threonine kinase IL-1 receptor associated kinases (IRAKs). The IRAK family has four members and the newest member, IRAK-4, is indispensable to the TIR-mediated signaling pathway. The improper regulation of TIR receptor signaling leads to the development of such severe inflammatory diseases as sepsis, asthma, rheumatoid arthritis and even cancer. Therefore, it is very important to determine precisely the implications of TIR signaling in those inflammatory diseases for appropriate medical treatment and drug development. As IRAK-4 is the critical molecule for TIR-mediated signaling, it is a promising therapeutic target for many inflammatory diseases. In this review, we discuss the functions of the IRAK family members with focus on IRAK-4, to seek the possibility of yielding new therapeutic strategies.