Multiple cellular mechanisms contribute to the overall clinical drug-resistant phenotype of malignant cells. A major mechanism of drug resistance documented to occur in hematologic malignancies is overexprssion of the MDR-1 gene product, P-glycoprotein (P-gp). Drugs, called chemosensitizers, have been designed to overcome P-gp-mediated drug resistance, and these agents are now being tested in the clinic. Overcoming P-gp-mediated resistance may select for alternative mechanisms of resistance that are not affected by chemosensitizing agents. Alternative mechanisms are now being described, and the clinical relevance of these mechanisms is being investigated in hematologic malignancies. The exact mechanisms involved in the overall drug-resistant phenotype will likely depend on the type of malignancy and its exposure to anticancer drugs. A major challenge in improving the treatment of patients with hematologic malignancies will be to determine if and when these various cellular mechanisms contribute to clinical drug resistance.