Some clinical features of rheumatoid arthritis (RA) (for example, preferential joint involvement and bilateral symmetry), taken together with the strong evidence of neurogenic inflammatory processes, suggest that the nervous system contributes to the inflammatory component of RA and other polyarthritides. The authors propose that the increased risk and severity of disease in particular joints reflects a greater innervation of those joints by unmyelinated afferent and sympathetic efferent fibers. Release of the proinflammatory peptide, substance P, from the peripheral terminals of nociceptive joint afferent fibers, through interactions with many nonneural cells, exacerbates the inflammatory process. Release of mediators from sympathetic efferents (including norepinephrine) also contributes to the inflammation, either through an independent mechanism or by acting in concert with the nociceptive afferent-derived substances. Therapies directed at interruption of the nervous system contribution to the pathophysiology of these diseases should offer a new direction to treatment.