Drug resistance represents a serious barrier to the successful treatment of hematological malignancies. In leukemias, resistance mechanisms that involve membrane-resident proteins belonging to the ABC (ATP-binding cassette) transporter protein family are of particular interest, wherein enhanced expression is often associated with poor prognosis and frequent in relapsed or refractory disease. These proteins reduce the intracellular concentration of antitumor agents, greatly diminishing clinical efficacy. Research in this area has been directed at the design of agents, “pump antagonists”, to overcome the effluxing capacity of drug transporters; however, this direction has had limited clinical success. An allied function of ABC transporters like P-glycoprotein (P-gp) is glycolipid trafficking, an area that has not been explored from a therapeutic standpoint. In this capacity, it turns out that glycolipid synthesis can be attenuated by pump antagonists; this is perhaps an adventitious property of P-gp. Recent research in the area of lipid metabolism, specifically ceramide and glycolipids, has provided insight into the function of glycosphingolipids in multidrug resistance and in the action of chemotherapy. This review is intended to bring together those aspects of glycosphingolipid metabolism that might be leveraged to enhance the therapeutic performance of ceramide and to discuss how ABC transporters like P-gp might be targeted to potentiate and magnify ceramide-driven proapoptotic cascades.