Multidrug resistance (MDR) is a pleiotropic resistance against several unrelated drugs. It may be induced by prolonged exposure of cells to drugs such as doxorubicin, etoposide and vinca alkaloids. Once MDR develops in clinical tumors, it is a major obstacle for the improvement of treatment of multiple myeloma (MM). Several specific mechanisms have been identified in clinical refractory MM patients including typical MDR, which is associated with P-glycoprotein (Pgp) and Lung Resistance Protein (LRP). The expression of the proteins associated with these genes seems to depend on exposure to chemotherapeutic agents. Recently, reversal of MDR by non-cytotoxic agents such as verapamil, cyclosporin A and PSC 833 (Valdospar) was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR is possible and that it may lead to alterations of the plasma pharmacokinetics of the cytostatic agents, in addition to P-glycoprotein inhibition in tumor cells. The potential implications of P-glycoprotein reversal are discussed.