Toll-like receptors (TLRs) are crucial components of the innate immune system, recognizing a wide array of molecular patterns to initiate immune responses. This review highlights the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. TLRs are structured with an N-terminal domain containing leucine-rich repeats (LRRs), a single transmembrane helix, and a C-terminal cytoplasmic Toll-interleukin-1 receptor (TIR) domain. They recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering signaling cascades that lead to the production of pro-inflammatory cytokines and type I interferons. TLRs play essential roles in infectious diseases, autoimmunity, chronic inflammation, and cancer, making them potential therapeutic targets. Recent advancements include the development of specific agonists and antagonists, which have shown promise in immunotherapy and vaccine development. However, challenges and controversies remain, including the complex roles of TLRs in various diseases and the need for further research in personalized medicine and computational modeling. Overall, TLRs represent a promising frontier in medical research, offering significant potential for novel therapeutic strategies.Toll-like receptors (TLRs) are crucial components of the innate immune system, recognizing a wide array of molecular patterns to initiate immune responses. This review highlights the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. TLRs are structured with an N-terminal domain containing leucine-rich repeats (LRRs), a single transmembrane helix, and a C-terminal cytoplasmic Toll-interleukin-1 receptor (TIR) domain. They recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering signaling cascades that lead to the production of pro-inflammatory cytokines and type I interferons. TLRs play essential roles in infectious diseases, autoimmunity, chronic inflammation, and cancer, making them potential therapeutic targets. Recent advancements include the development of specific agonists and antagonists, which have shown promise in immunotherapy and vaccine development. However, challenges and controversies remain, including the complex roles of TLRs in various diseases and the need for further research in personalized medicine and computational modeling. Overall, TLRs represent a promising frontier in medical research, offering significant potential for novel therapeutic strategies.