Lack of much interest by the pharmaceutical industry to venture into development of new antitrypanosomal drugs has been a major stimulus to an intensification of research into the few existing drugs. Those indicated for animal trypanosomiasis include: isometamidium, homidium and diminazene, used primarily against Trypanosoma congolense, T. vivax and T. brucei; and quinapyramine, mainly indicated for use against T. evansi infections. A great deal of research effort has focused on development of pharmacological and parasitological methodologies, which have considerably advanced our understanding on the efficacy, resistance, disposition and toxicological mechanisms of these drugs. While a clinical breakthrough has been made in the recent past, in the field of chemotherapy of T. evansi infections by the introduction of a new arsenic compound, melarsenoxide cysteamine, chemotherapy of T. simiae infections in pigs still remains a major challenge because the existing drugs are either ineffective or too toxic for economic use. Further research into the existing drugs is a prerequisite for their optimal usage in the overall effort of improving animal health and productivity through control of trypanosomiasis.