Amebic meningoencephalitis is an uncommon infection of the central nervous system (CNS), the consequences of which are devastating in the vast majority of patients. Although it is fortunate that few individuals are affected by the infection, with such a low incidence of the disease it has been difficult to develop and test treatment approaches that, with the appropriate implementation, could be broadly effective. As might be expected, the currently available information suggests the possibility that early diagnosis and treatment can result in improved survival and possible recovery. It is also possible that some ameba families and strains may be less pathogenic than others. In order to initiate potentially effective interventions during the early stages, it is necessary to be aware of the clinical and epidemiologic features that distinguish primary from secondary CNS amebic infection and of the various organisms that are associated with these forms of disease. This is not only true for patients with the more classical presentations of these infectious syndromes but also for those who are “culture negative” for common human CNS pathogens. Such information would assist greatly in further delineating the etiopathogenesis and spectrum of disease that is associated with amebic infection of the CNS, as well as potentially effective therapies.