Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.