The innate immune system provides a first line of host defense against many common microorganisms and is essential for the control of common bacterial infections. The cells of the innate immune system, including macrophages and neutrophils, also play a critical part in the initiation and subsequent direction of adaptive immune responses. The activation of the innate immune system relies on the recognition of pathogen-associated molecular patterns (PAMPS) by specific pattern-recognition receptors (PRRs). Owing to the inability to generate an infinite range of PRRs, evolution has probably favored the development of the germline-encoded PRRs that recognizes a limited set of PAMPs corresponding to relatively invariant structures of microorganisms, such as lipopolysaccharide (LPS) or peptidoglycan (PGN). The innate immune system uses a variety of PRRs that can be expressed on the cell surface and in the cytoplasm. The recognition of PAMPs by PRRs results in the activation of different intracellular signaling cascades, which in turn, leads to the expression of various effector molecules. These effector molecules include proinflammatory cytokines, including interleukin-1? (IL-1?) and tumor necrosis factor (TNF) that initiate inflammation and adaptive immune responses. However, a detailed understanding of the activation mechanism of innate immune response remains elusive. In order to understand the innate immune response in atomic detail, our group focuses on the important protein-protein interactions involved in cytoplasmic innate immune receptor-induced signal transduction mechanisms utilizing X-ray crystallographic method as a major tool.