The discovery of Toll-like receptors (TLRs) has revolutionized the field of innate immunity, leading to the 2011 Nobel Prize in Physiology or Medicine for Jules Hoffmann, Bruce Beutler, and Ralph Steinman. TLRs are pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The article traces the historical development of TLR research, from the identification of the IL-1 receptor (IL-1R) and the cell surface protein Toll in Drosophila melanogaster to the elucidation of TLR signaling pathways. Key milestones include the identification of mammalian TLR4 as the lipopolysaccharide (LPS) receptor, the discovery of other ligands for different TLRs, and the understanding of TLR signaling mechanisms. The article also discusses the role of TLRs in disease and therapeutic applications, highlighting the potential of TLR agonists and antagonists in treating infectious and inflammatory diseases. Despite significant progress, the true therapeutic potential of TLRs remains largely unexplored, and further research is needed to fully understand their functions and clinical implications.The discovery of Toll-like receptors (TLRs) has revolutionized the field of innate immunity, leading to the 2011 Nobel Prize in Physiology or Medicine for Jules Hoffmann, Bruce Beutler, and Ralph Steinman. TLRs are pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). The article traces the historical development of TLR research, from the identification of the IL-1 receptor (IL-1R) and the cell surface protein Toll in Drosophila melanogaster to the elucidation of TLR signaling pathways. Key milestones include the identification of mammalian TLR4 as the lipopolysaccharide (LPS) receptor, the discovery of other ligands for different TLRs, and the understanding of TLR signaling mechanisms. The article also discusses the role of TLRs in disease and therapeutic applications, highlighting the potential of TLR agonists and antagonists in treating infectious and inflammatory diseases. Despite significant progress, the true therapeutic potential of TLRs remains largely unexplored, and further research is needed to fully understand their functions and clinical implications.