Cadherin-11 has been identified as a key regulator of synovial architecture mediating contact between Fibroblast-like Synoviocytes and organization in the lining layer. A central role for cadherin-11 has also been suggested in the formation of the rheumatoid pannus. Therapeutic targeting of cadherin-11 results in amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. In addition, cadherin-11 expression is upregulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of cadherin-11 mRNA transcripts in the peripheral blood has been associated with more severe disease phenotypes in two prototypic conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis, respectively. Currently, a monoclonal antibody against cadherin-11 is in early phases of clinical trials in patients with rheumatoid arthritis. Herein, we review the current knowledge regarding the potential role of cadherin-11 in pathogenesis, as well as a biomarker and therapeutic target in chronic inflammatory rheumatic diseases.