Resistance to chemotherapy is a major obstacle in the treatment of patients with acute myeloid leukemia (AML). The majority of AML patients are intrinsically resistant to chemotherapy at initial diagnosis before chemotherapeutic exposure; such intrinsic resistance frequently results from expression of the multidrug resistance gene (MDR-1), which encodes a membrane transporter protein, P-glycoprotein (P-gp), that mediates drug efflux in leukemic cells. Expression of novel transporter proteins that confer alternative forms of multidrug resistance (MDR), such as the lung-resistance protein (LRP) and the MDR-associated protein (MRP), occurs more frequently in leukemic patients at relapse. Preliminary studies indicate that these proteins may also confer therapeutic resistance in leukemia. In patients older than 55 years of age, AML is characterized by a high frequency of unfavorable cytogenetics, P-gp expression, and functional drug efflux, which contribute to poor clinical outcome. In a multivariate analysis, secondary AML, unfavorable cytogenetics, and P-gp expression/function were each significantly and independently associated with a lower complete remission (CR) rate. Resistant disease was associated with P-gp expression and unfavorable cytogenetics. Strikingly, elderly patients with P-gp- de novo AML and favorable or intermediate cytogenetics had a CR rate of 81%. Patients with P-gp+ secondary AML with unfavorable cytogenetics had a CR rate of only 12%. Therefore, characterization of elderly AML patients at diagnosis using biologic parameters may help identify those patients who are likely to achieve a CR with conventional regimens, as well as those patients who require alternate treatment designed to overcome MDR. In contrast, expression of P-gp and functional drug efflux is detected in only 25% to 30% of AML patients less than 50 years of age. While P-gp expression is less strongly associated with a poor outcome in younger versus older AML patients, it remains strongly associated with resistant disease. Studies are ongoing to determine the prognostic significance of LRP and MRP in various forms of leukemia.