Drug resistance in African trypanosomes continues to confound clinicians and to stymy development o f equatorial Africa, taking its toll in lives and economic development. Drugs in current, widespread use have been employed continuously for over 60 years in some instances. The recent studies of Fairlamb and colleagues have outlined a defective purine-transport system in drug-resistant trypanosomes, which appears to explain resistance to several established tryponocides and suggests a guide for the development of new drugs. The recently developed agent dl-alpha-di fluoromethylornithine (DFMO) is effective against West African, but not East African, disease and its activity may be the result of the unregulated synthesis of S-odenosylmethionine in tryponosomes. In this report, Cyrus Bacchi outlines recent developments in the elucidation of mechanisms of resistance to established drugs and naturally occurring resistance to DFMO.