Lysosomes were first described as vacuolar structures containing various hydrolytic enzymes at acidic pH. Subsequent studies revealed that the lysosome/vacuolar system is complex and composed of distinct membrane-enclosed vesicles including endosomes, primary and mature lysosomes, autophagic vesicles, residual bodies, multivesicular bodies, and digestive lysosomes. Lysosomes express a battery of hydrolytic enzymes including proteases, acid phosphatases, glycosidases, and lipases. Parasitic protozoa also possess complex intracellular lysosomes/endosomes/vesicles involved in digestion, transport and recycling of molecules similar to those of mammalian cells. Unique characteristics are ascribed to lysosomes of different parasites and may even differ between parasite stages. Transport of hydrolases and proteins to parasite lysosomes is directed either from the Golgi complex via endosomal vesicles or from endocytic vesicles originated in the cell surface. Inhibition of lysosomal proteases demonstrated that different proteolytic machineries catabolize distinct classes of proteins, and this selectivity may be exploited for the development of effective antiparasitic drugs. This review describes lysosomal molecules that are either validated or potential drug targets for Chagas disease, sleeping sickness, leishmaniasis, toxoplasmosis, malaria, amebiasis, and giardiasis.