Members of the Toll-like receptor (TLR) family play key roles in both innate and adaptive immune responses. TLR proteins enable host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharides, viral RNA, CPG-containing DNA, and flagellin, among others. TLRs are also apparently able to mediate responses to host molecules, including one defensin, ROS, HMGB1 (high-mobility group box protein 1), surfactant protein A, fibrinogen, breakdown products of tissue matrix, heat shock proteins (hsp) and eosinophil-derived neurotoxin (EDN). Thus, TLR are involved in the development of many pathological conditions including infectious diseases, tissue damage, autoimmune and neurodegenerative diseases and cancer. In this review, the contribution of TLRs to diseases of the central nervous system (CNS), lung, gastrointestinal tract, kidney and skin as well as cancer is evaluated. We hope to provide new insight into the pathogenesis and progression of diseases and more importantly, into the potential for TLRs as targets of therapeutics.