Because drug resistance is a barrier to the cure of many neoplastic diseases, identification of mechanisms of resistance to different classes of anticancer drugs and development of assays to recognize individual drug-resistant tumor cells are justified. We have focused our recent efforts on cells expressing multidrug resistance due to altered (decreased) activity of DNA topoisomerase II (at-MDR). We discuss herein molecular and cellular assays that permit the detection of single cells expressing the at-MDR phenotype, and suggest that these assays may have more general applicability to cells expressing other mechanisms of multidrug resistance.