The article by Takumi Kawasaki and Taro Kawai provides an in-depth review of Toll-like receptor (TLR) signaling pathways, which are crucial for the innate immune response to microbial infections. TLRs are pattern-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the activation of downstream signaling pathways that induce inflammatory responses and protect the host from microbial infection. The authors discuss the classification of TLRs into cell surface and intracellular subfamilies, their recognition of microbial components, and the importance of proper cellular localization for ligand recognition and autoimmunity prevention. They also detail the trafficking of TLRs, the role of adaptor proteins such as MyD88 and TRIF in signal transduction, and the regulation of TLR signaling by negative regulators. The article highlights recent progress in understanding the complex mechanisms of TLR signaling, including the involvement of lipid mediators, ubiquitination, and mRNA stability. Finally, it explores the implications of TLR signaling in diseases such as autoimmune disorders, chronic inflammation, and cancer, emphasizing the potential therapeutic strategies that could be developed based on a better understanding of these pathways.The article by Takumi Kawasaki and Taro Kawai provides an in-depth review of Toll-like receptor (TLR) signaling pathways, which are crucial for the innate immune response to microbial infections. TLRs are pattern-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the activation of downstream signaling pathways that induce inflammatory responses and protect the host from microbial infection. The authors discuss the classification of TLRs into cell surface and intracellular subfamilies, their recognition of microbial components, and the importance of proper cellular localization for ligand recognition and autoimmunity prevention. They also detail the trafficking of TLRs, the role of adaptor proteins such as MyD88 and TRIF in signal transduction, and the regulation of TLR signaling by negative regulators. The article highlights recent progress in understanding the complex mechanisms of TLR signaling, including the involvement of lipid mediators, ubiquitination, and mRNA stability. Finally, it explores the implications of TLR signaling in diseases such as autoimmune disorders, chronic inflammation, and cancer, emphasizing the potential therapeutic strategies that could be developed based on a better understanding of these pathways.