Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and plays a crucial role in initiating innate immune responses. The recognition of LPS is mediated by a cascade of receptors and accessory proteins, including LPS binding protein (LBP), CD14, and the Toll-like receptor 4 (TLR4)–MD-2 complex. These proteins recognize the common structural patterns of LPS across diverse bacterial species, enabling the immune system to differentiate LPS from host molecules. The structures of these proteins provide insights into how they recognize LPS and contribute to the development of anti-sepsis drugs. This review summarizes the structures of these proteins and discusses the structural basis of LPS recognition by LPS receptors and accessory proteins. The structures of the TLR4–MD-2 complex, LBP, and CD14 are described, along with their implications for understanding TLR4–MD-2 activation in response to LPS recognition. The article also covers the structure of LPS, the binding of LPS to the TLR4–MD-2 complex, and the activation of the TLR4–MD-2 complex through dimerization and signaling adaptor recruitment. Additionally, the structures of other TLRs and the hybrid LRR technique for crystallizing TLR family proteins are discussed. The findings contribute to the development of novel therapeutic agents that can either attenuate or enhance TLR-mediated signaling.Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and plays a crucial role in initiating innate immune responses. The recognition of LPS is mediated by a cascade of receptors and accessory proteins, including LPS binding protein (LBP), CD14, and the Toll-like receptor 4 (TLR4)–MD-2 complex. These proteins recognize the common structural patterns of LPS across diverse bacterial species, enabling the immune system to differentiate LPS from host molecules. The structures of these proteins provide insights into how they recognize LPS and contribute to the development of anti-sepsis drugs. This review summarizes the structures of these proteins and discusses the structural basis of LPS recognition by LPS receptors and accessory proteins. The structures of the TLR4–MD-2 complex, LBP, and CD14 are described, along with their implications for understanding TLR4–MD-2 activation in response to LPS recognition. The article also covers the structure of LPS, the binding of LPS to the TLR4–MD-2 complex, and the activation of the TLR4–MD-2 complex through dimerization and signaling adaptor recruitment. Additionally, the structures of other TLRs and the hybrid LRR technique for crystallizing TLR family proteins are discussed. The findings contribute to the development of novel therapeutic agents that can either attenuate or enhance TLR-mediated signaling.