Multidrug resistance, mediated by the P-glycoprotein 170 transport pump, is a serious problem in multiple myeloma. In this review we discuss the expression of P-gp as a differentiation antigen on normal T and B lymphocytes. In myeloma, circulating presumptively malignant B cells express P-gp prior to chemotherapy. A variety of evidence characterizes these circulating B cells as members of the malignant clone in myeloma, including the demonstration that they share immunoglobulin heavy chain (IgH) rearrangements with bone marrow plasma cells, and their extensive DNA aneuploidy. In some patients the only components of the clonal populations that express P-gp are the circulating B cells suggesting that they represent a reservoir of multidrug resistant cells that maintain malignant growth and spread in myeloma. We speculate that exposure to chemotherapy alters clonal homeostasis and exerts positive selection pressure on generative components of the myeloma clone. Thus the possibility exists that chemotherapy perpetuates rather than eradicates myeloma stem cells. P-gp is detectable on bone marrow plasma cells in myeloma but appears to be in an inactive form that is unable to mediate efflux of marker dyes. A similar phenomenon is seen for normal human monocytes which have surface P-gp but lack any functional export of P-gp substrates. P-gp appears to vary depending in a cell-type specific manner suggesting that it may be feasible to design inhibitors of P-gp which selectively block P-gp export by malignant cells and spare the function of P-gp on normal tissue, including lymphocytes and normal hematopoietic stem cells.