Understanding the pathogenesis of joint inflammation and destruction in rheumatoid arthritis involves dissection of the cellular and molecular interactions that occur in synovial tissue. Development of effective targeted therapies has been based on progress in achieving such insights. Safer and more specific approaches to treatment could flow from discovery of cell-cell interaction pathways that are specific to inflammation of the joint and less important in the defense against systemic infection. This article highlights selected cell-cell interactions in rheumatoid arthritis synovium that may be worthy of evaluation as future therapeutic targets.