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It is an awkward issue to treat systemic lupus erythematosus ��SLE�� in patients with corticosteroid unresponsiveness. Recently, P-glycoprotein ��P-gp�� and macrophage migration inhibition factor ��MIF�� have been clearly linked to the modulation of corticosteroid sensitivity. The following two mechanisms seem to be involved in corticosteroid unresponsiveness. First, over-expression of P-gp on activated peripheral lymphocytes can cause the exclusion of intercellular corticosteroid from lymphocytes. Second, the expression of MIF, which exerts a potent antagonistic effect on corticosteroid suppression of immune-mediated inflammation, is increased in patients with SLE. It may restore the sensitivity to corticosteroid to down-regulate or suppress the expression of P-gp and MIF in patients with SLE.