In this review we discuss the mechanisms and molecules involved in the multidrug resistance (MDR) of the protozoan parasite Entamoeba histolytica. Drug resistant mutants exhibited the main characteristics presented by the MDR mammalian cells. They showed cross-resistance to several unrelated drugs that is reverted by calcium channel blockers. MDR phenotype in E. histolytica is regulated at a transcriptional level by the EhPgp1 gene, which is constitutively expressed and by the EhPgp5 gene, whose expression is induced in the presence of the drug. Transcription factors participate in the expression regulation of these genes. After over transcription, the EhPgp genes are amplified, cooperating to produce the MDR phenotype. Post-transcriptional mechanisms such as mRNA stability seem to be involved in this phenomenon. As for other mdr gene products, the EhPGP5 protein functions as a chloride current inductor or as a regulator of cellular regulatory volume decrease.