Evidence for the phenomenon of multiple drug resistance (MDR) in the well studied pathogenic protozoa has been examined. This has been placed in the more familiar context of the MDR efflux transporters and the cloned mdr genes of mammalian cells. Homologues of the mdr gene family in protozoa and their possible role in drug efflux have been compared with their mammalian counterparts. Possible mechanisms and models for drug efflux have been considered. The unusual and extensive range of substrates transported by the ATP-binding cassette (ABC) family of transporters which includes the MDRs has been raised. The impact of kinetics, structure and bioenergetics of the MDR family members on mechanisms of transport has been accentuated to argue that MDR efflux considered in isolation appears bizarre but may be better understood in a broader context.