Rheumatoid arthritis (RA) is a systemic autoimmune disease manifesting in joint destruction. The recognized hallmark of RA pathogenesis is the involvement of immune cells which produce many mediators potentiating an inflammatory environment. RA synovial fibroblasts (RASFs) contribute significantly to disease progression by initiating and regulating many pathways of joint destruction. Detailed molecular insights into RASF biology may lead to identification of important therapeutic targets. The discovery of common molecular targets for joint resident and inflammatory cells may help to develop the most effective therapeutic strategy. One such pathway includes semaphorin 4A as reported in a recent article in Arthritis Research & Therapy.