Pathogenic free-living amebas of the genera Naegleria and Acanthamoeba and the leptomyxid ameba of the order Leptomyxida may be capable of producing disease in the central nervous system of human beings and animals. These amebas are distributed worldwide in thermally polluted streams, coastal and fresh water, dust, soil, and sewage, and heating, ventilating, and air conditioning units. N. fowleri may produce primary amebic meningoencephalitis, a rapidly fatal central nervous system infection. By contrast, the Acanthamoeba spp. and the recently described leptomyxid ameba may produce granulomatous amebic encephalitis, a protracted central nervous system disease, usually in immunocompromised hosts. The leptomyxid ameba may produce clinical symptoms similar to and histopathologic features almost identical to those in GAE. Contact-lens wearers may also develop Acanthamoeba keratitis, chronic ulceration of the corneal epithelium due to Acanthamoeba spp. The various central nervous system diseases produced by these free-living amebas result in divergent epidemiological patterns, diverse clinical manifestations, and distinct pathological features, and require different treatment.