Entamoeba histolytica is the causative agent of amebiasis, a disease that is a major source of morbidity and mortality in the developing world. The potent cytotoxic activity of the parasite appears to underlie disease pathogenesis, although the mechanism is unknown. Recently, progress has been made in determining that the parasite activates apoptosis in target cells and some putative effectors have been identified. Recent studies have also begun to unravel the host genetic determinants that influence infection outcome. Thus, we are beginning to get a clearer picture of how this parasite manages to infect, invade and ultimately inflict devastating tissue destruction.