Multidrug resistance in hematologic malignancies and some solid tumors is mediated by a cell membrane pump known as the P-glycoprotein (P-gp). P-gp rapidly transports a variety of heterocyclic agents (including many natural product antiproliferative drugs) out of tumor cells thus abrogating their anticancer effects. P-gp can be competitively inhibited by exposure to antirheumatic drugs including antimalarials and cyclosporin A. Such inhibitors are being used as chemosensitizers (CS) to enhance the effects of chemotherapy in drug resistant tumors. P-gp is also expressed by some normal cells including macrophages and cytotoxic lymphocytes. Recent studies of purified natural killer (NK) cells have shown that both the drug efflux and NK cytotoxic functions can be inhibited by CS agents, suggesting that both drug efflux and cytotoxicity may be mediated by P-gp's molecular transport function. NK cell cytotoxicity is mediated by secreted molecules such as granzymes and perforins. Both tumor necrosis factor alpha (TNF-alpha) producing macrophages and NK cells are present in the synovial tissues and fluid in early and advanced rheumatoid arthritis (RA). We hypothesize that antiarthritic effects of the antimalarials and cyclosporine and perhaps glucocorticoids are partially attributable to the inhibition of P-gp function thereby blocking TNF-alpha release by macrophages, TNF-alpha activation of NK cells, and NK cell secretion of cytotoxins in the rheumatoid joint. This hypothesis permits the mechanism of action of some antirheumatic drugs to be classified, and may aid in the development of combination therapy for RA and other autoimmune disorders.