Toll-like receptors (TLR) that belong to the group of protein recognition receptor (PPR) provide an innate immune response following the sensing of conserved pathogen-associated microbial patterns (PAMPs) and changes in danger-associated molecular patterns (DAMPs) that are generated as a consequence of cellular injury. Analysis of the TLR pathway has moreover offered new insights into the pathogenesis of rheumatoid arthritis (RA). Indeed, a dysfunctional TLR-mediated response characterizes RA patients and participates in establishment of a chronic inflammatory state. Such an inappropriate TLR response has been attributed (i) to the report of important alterations in the microbiota and abnormal responses to infectious agents as part of RA; (ii) to the abnormal presence of TLR-ligands in the serum and synovial fluid of RA patients; (iii) to the overexpression of TLR molecules; (iv) to the production of a large panel of pro-inflammatory cytokines downstream of the TLR pathway; and (v) to genetic variants and epigenetic factors in susceptible RA patients promoting a hyper TLR response. As a consequence, the development of promising therapeutic strategies targeting TLRs for the treatment and prevention of RA is emerging.