In this review we present our search for the presence of drug targets in several species of human pathogenic parasites, mainly the amoebas Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri. We started with an analysis of the concepts of essentiality and validity of the targets and continue with a description of the main characteristics of pathogenicity of these amoebas. We then proceed to evaluate these targets arranged mainly in seven groups corresponding to: a) enzymes which are secreted by these parasites to invade the human host, for example proteinases, phospholipases and pore forming peptides, b) glycolytic enzymes from Entamoeba and Naegleria, like the PPi-dependent phospho-fructokinase that differ from the host enzyme, c) thiols and enzymes of redox metabolism, present only in trypanosomatids, Entamoeba and Naegleria, such as the trypanothione/trypanothione reductase that maintains the reducing environment within the cell, d) antioxidant enzymes to regulate the oxidative stress produced by the phagocytic cells of the host or by the parasite metabolism, like the trypanothione peroxidase in connection with the NADPH-dependent trypanothione/trypanothione reductase which maybe is present in Naegleria fowleri, and peroxiredoxin in E. histolytica, e) enzymes for the synthesis of trypanothione like the ornithine decarboxylase, spermidine synthase and trypanothione synthetase, f) some of the proteins that assemble the secretory vesicles with the cell membrane, like the synaptobrevins and finally, g) encystment pathways and cyst-wall assembly proteins. Some of the above new targets will need to be studied in a more detail, including crystallographic studies of the enzymes for rational drug design. As far as we know there are no advanced crystallographic studies being conducted on targets from these three amoebas, as has been the case for various targets from the trypanosomatids.