Entamoeba histolytica is an enteric dwelling human protozoan parasite that causes the disease amoebiasis, which is endemic in the developing world. Over the past four decades, considerable effort has been made to understand the parasite and the disease. Improved diagnostics can now differentiate pathogenic E. histolytica from that of the related but nonpathogenic Entamoeba dispar, thus minimizing screening errors. Classically, the triad of Gal-lectin, cysteine proteinases and amoebapores of the parasite were thought to be the major proteins involved in the pathogenesis of amoebiasis. However, other amoebic molecules such as lipophosphopeptidoglycan, perioxiredoxin, arginase, and lysine and glutamic acid-rich proteins are also implicated. Recently, the genome of E. histolytica has been sequenced, which has widened our scope to study additional virulence factors. E. histolytica genome-based approaches have now confirmed the presence of Golgi apparatus-like vesicles and the machinery for glycosylation, thus improving the chances of identifying potential drug targets for chemotherapeutic intervention. Apart from Gal-lectin-based vaccines, promising vaccine targets such as serine-rich E. histolytica protein have yielded encouraging results. Considerable efforts have also been made to skew vaccination responses towards appropriate T-helper cell immunity that could augment the efficacy of vaccine candidates under study. Thus, ongoing efforts mining the information made available with the sequencing of the E. histolytica genome will no doubt identify and characterize other important potential vaccine/drug targets and lead to effective immunologic strategies for the control of amoebiasis.