American (Chagas' disease) and African (sleeping sickness) trypanosomiasis are diseases that are endemic in parts of Latin American and Africa, respectively. Physicians in developed countries may occasionally see cases because of extensive travel and immigration from endemic countries. In addition, in American trypanosomiasis, transmission via contaminated blood transfusions poses significant risks of causing acute Chagas' disease in immunocompromised patients. Both forms of trypanosomiasis have neurologic manifestations. Chagas' disease can present as acute meningoencephalitis in children and some immunocompromised patients. Additionally, there are increasingly frequent reports of neurologic syndromes, including CNS mass lesions, in HIV-infected patients. African sleeping sickness has prominent CNS pathologic features in stage II disease. Proposed pathogenetic mechanisms and diagnostic and therapeutic considerations are reviewed in this article.