Toll-like receptors (TLRs) are the immune sensors for infections, triggering robust innate immune activation followed by protective adaptive immunity against various infectious diseases. Recent evidence, however, has suggested that TLRs are involved in the pathogenesis of many diseases, including not only infectious diseases but also autoimmune diseases, allergy and atherosclerosis. Therefore, prophylactic or therapeutic application of TLR-based immune interventions should be potent, but their safety must be demonstrated using experimental animal models as well as human resources, including analysis of single nucleotide polymorphisms. Here, we focus on recent advances in understanding of the protective and pathogenic roles of TLRs in human diseases.