Toll-like receptors (TLRs) play a crucial role in the detection of pathogen-associated mol. patterns (PAMPs) and in the subsequent activation of immune responses. In autoimmune diseases, endosomal TLRs recognize damage-associated mol. patterns (DAMPs) and induce pro-inflammatory Th1, Th17, and inflammasome signaling cascades, which exacerbate the disease. Targeting Toll-like receptors provides a novel approach to inhibiting DAMP-associated inflammatory signaling. We have designed synthetic oligonucleotide-based antagonists of the endosomal TLRs 7, 8, and 9 (J. Med. Chem. 2009, 52, 551-558) that block TLR recognition of DAMPs and have shown activity in preclin. models of psoriasis (JID, 2013, 133: 1777-1784), lupus (Autoimmunity, 2013, 46(7): 419-428), and other autoimmune and inflammatory diseases. To establish clin. proof-of-concept of TLR antagonism, we have evaluated two drug candidates, IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8, and 9, in patients with moderate to severe plaque psoriasis. In these randomized, double blind, placebo controlled trials, weekly treatment for 4 to 12 wk was well tolerated. Treatment led to significant improvements in Psoriasis Area and Severity Index (PASI) scores, dermal thickness, and immunol. markers in the psoriatic lesions. PASI improvements were correlated with down-regulation of IL-17 gene profile. Endosomal DAMPS are implicated in diverse diseases in which TLR antagonism may provide a novel approach to treatment; for example, B-cell lymphomas harboring the MYD88 L265P mutation, which leads to over-activation of the TLR7 and 9 pathways. Other examples include Duchenne muscular dystrophy (DMD), in which TLR7-mediated signaling is implicated in the inflammatory cycle. Clin. development of IMO-8400 in B-cell lymphomas harboring MYD88 L265P is in progress, and encouraging preclin. data of TLR antagonism in DMD has been reported. Further update on these developments will be discussed. TLR antagonism provides a novel therapeutic approach for the treatment of diverse diseases by blocking the induction of pro-inflammatory cytokines and immune signaling cascades.