The mammalian innate immune system detects microbial infections through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid-inducible gene-I-like receptors (RLRs), and nucleotide-binding oligomerization domain-like receptors (NLRs). These PRRs recognize different but overlapping microbial components and are expressed in various cellular compartments, such as the cell surface, endosomes, lysosomes, or cytoplasm. They activate specific signaling pathways that lead to the expression of genes that tailor immune responses to particular microbes. TLRs are type I transmembrane proteins composed of three major domains: an ectodomain with leucine-rich repeats (LRRs) that mediate PAMP recognition, a transmembrane domain, and an intracellular domain with a Toll/IL-1 receptor (TIR) domain required for downstream signaling. TLRs detect a wide range of PAMPs, including lipids, lipoproteins, proteins, glycans, and nucleic acids. TLR4, for example, recognizes bacterial lipopolysaccharide (LPS) and forms a complex with MD-2 to activate signaling pathways that induce inflammatory cytokines and type I interferons (IFNs). RLRs, such as RIG-I and MDA5, belong to the RNA helicase family and specifically detect viral RNA in the cytoplasm. Upon recognition of viral RNA, RLRs coordinate anti-viral programs by inducing type I IFNs and inflammatory cytokines. NLRs, including NOD1, NOD2, and NALP3, are intracellular PRRs that recognize bacterial cell products and form multi-protein complexes, such as the NALP3 inflammasome, which promotes the release of IL-1 family cytokines. The signaling pathways initiated by TLRs, RLRs, and NLRs converge on the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs), which regulate the expression of immune and inflammatory genes. Additionally, some TLRs and RLRs can activate members of the interferon regulatory factor (IRF) family, which induce the expression of type I IFNs and inflammatory genes. Recent studies have also identified an as-yet-undefined cytosolic DNA sensor that recognizes double-stranded DNA (dsDNA) released by certain viruses or bacteria and triggers type I IFN responses via the activation of TBK1 and IKK complex. STING, a membrane protein expressed in the endoplasmic reticulum (ER), has been identified as a potential sensor for cytosolic dsDNA and plays a crucial role in activating the IFNβ promoter. Overall, the roles of TLRs, RLRs, and NLRs in pathogen recognition and their signaling pathways are essential for the innate immune response to microbial infections.The mammalian innate immune system detects microbial infections through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid-inducible gene-I-like receptors (RLRs), and nucleotide-binding oligomerization domain-like receptors (NLRs). These PRRs recognize different but overlapping microbial components and are expressed in various cellular compartments, such as the cell surface, endosomes, lysosomes, or cytoplasm. They activate specific signaling pathways that lead to the expression of genes that tailor immune responses to particular microbes. TLRs are type I transmembrane proteins composed of three major domains: an ectodomain with leucine-rich repeats (LRRs) that mediate PAMP recognition, a transmembrane domain, and an intracellular domain with a Toll/IL-1 receptor (TIR) domain required for downstream signaling. TLRs detect a wide range of PAMPs, including lipids, lipoproteins, proteins, glycans, and nucleic acids. TLR4, for example, recognizes bacterial lipopolysaccharide (LPS) and forms a complex with MD-2 to activate signaling pathways that induce inflammatory cytokines and type I interferons (IFNs). RLRs, such as RIG-I and MDA5, belong to the RNA helicase family and specifically detect viral RNA in the cytoplasm. Upon recognition of viral RNA, RLRs coordinate anti-viral programs by inducing type I IFNs and inflammatory cytokines. NLRs, including NOD1, NOD2, and NALP3, are intracellular PRRs that recognize bacterial cell products and form multi-protein complexes, such as the NALP3 inflammasome, which promotes the release of IL-1 family cytokines. The signaling pathways initiated by TLRs, RLRs, and NLRs converge on the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs), which regulate the expression of immune and inflammatory genes. Additionally, some TLRs and RLRs can activate members of the interferon regulatory factor (IRF) family, which induce the expression of type I IFNs and inflammatory genes. Recent studies have also identified an as-yet-undefined cytosolic DNA sensor that recognizes double-stranded DNA (dsDNA) released by certain viruses or bacteria and triggers type I IFN responses via the activation of TBK1 and IKK complex. STING, a membrane protein expressed in the endoplasmic reticulum (ER), has been identified as a potential sensor for cytosolic dsDNA and plays a crucial role in activating the IFNβ promoter. Overall, the roles of TLRs, RLRs, and NLRs in pathogen recognition and their signaling pathways are essential for the innate immune response to microbial infections.