Toll-like receptors (TLRs) are crucial for innate immunity, recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling involves adaptor proteins like MyD88 and TRIF, leading to activation of NF-κB and IRFs, which regulate immune responses. TLRs are divided into cell surface and intracellular types, with distinct roles in recognizing different pathogens. TLR signaling pathways include MyD88-dependent and TRIF-dependent pathways, which lead to inflammatory responses and type I interferon production. TLR signaling is regulated by various factors, including adaptor proteins, ubiquitination, and negative regulators that prevent excessive immune responses. Recent studies highlight the importance of TLR trafficking, cleavage, and protein modifications in signaling. TLR signaling also plays a role in autoimmune and inflammatory diseases, and its dysregulation can contribute to cancer development. Understanding TLR signaling pathways is essential for developing strategies to treat infectious and autoimmune diseases, as well as cancer.Toll-like receptors (TLRs) are crucial for innate immunity, recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling involves adaptor proteins like MyD88 and TRIF, leading to activation of NF-κB and IRFs, which regulate immune responses. TLRs are divided into cell surface and intracellular types, with distinct roles in recognizing different pathogens. TLR signaling pathways include MyD88-dependent and TRIF-dependent pathways, which lead to inflammatory responses and type I interferon production. TLR signaling is regulated by various factors, including adaptor proteins, ubiquitination, and negative regulators that prevent excessive immune responses. Recent studies highlight the importance of TLR trafficking, cleavage, and protein modifications in signaling. TLR signaling also plays a role in autoimmune and inflammatory diseases, and its dysregulation can contribute to cancer development. Understanding TLR signaling pathways is essential for developing strategies to treat infectious and autoimmune diseases, as well as cancer.