Amebic encephalitis caused by Balamuthia spp is an increasingly recognized chronic granulomatous central nervous system infectious process, which may affect both immunocompetent and immunocompromised individuals. The course of the disease is insidious and fatal in most cases, mainly due to delayed diagnosis, difficulty in isolation and/or identification of the organism, and lack of well-established amebicidal therapeutic regimens. This article reviews the clinicopathologic characteristics of infections caused by Balamuthia mandrillaris compared to other pathogenic free-living amebae and summarizes the latest diagnostic and therapeutic advances in infections caused by Balamuthia spp.