The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer. We postulate that increased sphingomyelin content, which develops early in some cancers, recruits, and functionalizes plasma membrane ABCB1 to confer a state of partial MDR, which is completed by increased glucosylceramide synthase activity and the redistribution of ABCB1 to intracellular vesicles. Moreover, concomitant upregulation of ABCB1 and the proapoptotic sphingolipid, ceramide, which is in turn extruded by ABCB1, culminates in increased drug resistance in renal cancer cells. In addition, the balance of differing ceramide species switches in MDR, favoring ceramides with longer fatty acid chain lengths, which may be crucial for the accommodation of drug transporters into the membrane bilayer. Recent data concerning the multifaceted roles of sphingolipid metabolizing enzymes and sphingolipid-dependence of normal and mislocalized ABCB1 expression and activity in the context of MDR and tumor cell survival will be presented and discussed.