Drug resistance has emerged as a devasting impediment to the treatment and control of diseases of parasitic origin. The underlying mechanisms that contribute to this drug resistance in field isolates, however, are poorly understood. Members of the P-glycoprotein gene (pgp) family have been identified, cloned, and sequenced in Plasmodia, Leishmania, and Entamoeba, and variations in pgp copy number and/or expression have been implicated as a basis for drug resistance in each of these genera. The spectrum of drugs to which parasitic protozoa containing amplified pgp genes and/or transcripts are refractory range from a phenotype similar to that observed with multidrug-resistant mammalian cells to those that are completely distinct. The availability of molecular probes to pgp genes provides valuable reagents to dissect the role of pgp gene amplification and overexpression in mediating drug resistance in parasitic protozoa and to determine the physiological function of P-glycoproteins in this clinically consequential group of human pathogens.