Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Genetic and epidemiologic studies point to a relevant role of adaptive T-cell response interactions with environmental factors such as smoking in the immunopathogenesis of the disease. These interactions result in a specific systemic autoantibody response that seems to contribute to the synovial inflammatory process. The reasons for specific localization of the autoimmune proinflammatory process to synovial tissue remain poorly known, but relevant local effector mechanisms have been recently unveiled and successfully targeted by new specific therapies. A relevant role for cytokine networks, where TNF-α displays a pivotal role, has been confirmed. The local pathology is hallmarked by immune cell accumulation and expansion of resident stromal and vascular cells. Crosstalk between these elements generates an aggressive environment that leads to cartilage and bone destruction. RA provides represents a model for systemic T-cell mediated systemic autoimmunity leading to local cellular and autoantibody mediated chronic inflammation. Whereas targeting of these elements with specific antagonists may interfere with the disease process, reestablishing tolerance and preventing further synovial inflammation has not been achieved.