The mechanism of action of drugs currently used to treat African trypanosomiasis is largely unknown. Alsford et al. used genome-scale RNA interference target sequencing screens in Trypanosoma brucei to identify the genes that contribute to the action of currently used drugs. In addition to known drug transporters, they linked over 50 genes to drug action; for example, a bloodstream-stage-specific invariant surface glycoprotein (ISG75) family was found to mediate the uptake of suramin. These findings could aid the rational design of new therapies for African trypanosomiasis and help to combat drug resistance.