Amoebae may be viewed as primitive, actively phagocytosing eukaryotic cells, many of which use bacteria as a major nutrient source. At a very archaic level, amoebae exert mechanisms which kill bacteria comparable to those found in phagocytic cells of higher organisms. Accordingly, it is tempting to suggest that the ancestors of effector cells of the innate immune system were bacteria-feeding amoebae and that their molecular armament is ancient. Here, we summarize the characteristics of antimicrobial and cytolytic 77-residue polypeptides from the protozoon Entamoeba histolytica for which correlates were found in effector cells of the mammalian immune systems. Based on the current knowledge about these small membrane-destabilizing proteins of phylogenetically extremely diverse origin, we discuss similarities and differences in their structure and activities.