The melaminophenyl arsenical melarsoprol is still used to treat African sleeping sickness, a disease caused by parasitic protozoa of the Trypanosoma brucei subgroup. Based on the observation that melamine antagonizes the trypanocidal activity of this class of drugs, we investigated whether other physiological compounds could compete for the same receptor. Here we report that the in vitro trypanolytic effect of melarsen oxide can be specifically abrogated by adenine, adenosine and dipyridamole, all of which compete for uptake by an adenosine transporter. Melarsen-sensitive trypanosomes have two high-affinity adenosine transport systems: a P1 type, which also transports inosine; and a P2 type, which also transports adenine and the melaminophenyl arsenicals. Melarsen-resistant trypanosomes lack P2 adenosine transport, suggesting that resistance to these arsenicals is due to loss of uptake.