The extracellular cysteine proteinases of Entamoeba histolyticahave been implicated as important virulence factors in the pathogenesis of amebiasis and play a key role in tissue invasion and disruption of host defenses. These proteinases have attracted considerable interest as targets for novel therapeutic agents and as vaccine candidates. Here, Xuchu Que and Sharon Reed highlight some of the more recent findings, focusing in particular on functional and structural features of the extracellular cysteine proteinases of E. histolytica.