Leishmaniasis, Chagas' disease, and African trypanosomiasis (sleeping sickness) pose substantial therapeutic challenges. In most situations, stibogluconate sodium and meglumine antimoniate, both pentavalent antimonials, remain the treatment of choice for leishmaniasis. However, reports of treatment failures are increasing as a result of both antimony resistance and infections in AIDS patients. Dosage recommendations have recently been increased. Amphotericin B and pentamidine are the standard alternatives, but are toxic. Recent clinical studies have focused on the efficacy of recombinant human interferon-γ used with a pentavalent antimonial, allopurinol, ketoconazole, and itraconazole. New experimental approaches designed to target drugs specifically to macrophages by complexing the drug with lipids, as in the case of amphotericin B, or with other moieties offer promise for the future.There have been no recent major advances in the treatment of Chagas' disease. A particularly important development in the treatment of West African sleeping sickness is eflomithine, which is safe and effective even for patients with advanced central nervous system infection. Unfortunately, the drug is not as effective in treating East African sleeping sickness and the search for more effective and safer drugs continues.