Multiple myeloma is a monoclonal plasma cell neoplasm that usually responds to chemotherapy but subsequently becomes drug resistant. Doxorubicin is a commonly used drug for myeloma, but its use leads to the development of resistant cells that express the MDR-1 membrane pump which actively extrudes doxorubicin and other agents from the cytoplasm of resistant cells. Patients resistant to doxorubicin often show resistance to many other drugs, some of which do not appear to be extruded by the MDR-1 pump mechanism. We used cDNA microarrays to evaluate the relative expression of approximately 5,700 human genes in a human multiple myeloma cell line (8226) and its doxorubicin-resistant subline (8226/D40). The mRNA expression profiles were performed in duplicate. As expected, the mRNA encoding the multidrug resistance gene MDR1 was markedly increased in 8226/D40 versus 8226. Overall, 1%–2% of the 5,700 genes analysed were differentially expressed, including a variety of genes not thought to be directly related to the MDR1 mechanism. Other genes affected by doxorubicin selection included N1 spermine/spermidine acetyltransferase, CD10 and raf. These observations suggest that changes in the expression of genes other than MDR1 may participate in the emergence of the multidrug resistant phenotype. Identification of such genes provides a basis for hypothesis generation with respect to their roles in multidrug resistance.