Sleeping sickness is an increasing problem in many parts of sub-Saharan Africa. The problems are compounded by the lack of new medication, and the increasing resistance against traditional drugs such as melarsoprol, berenil and isometamidium. Over the last few years, much progress has been made in understanding how drug action, and the development of resistance, is related to the mechanisms by which the parasite ingests the drugs. In some cases novel transporters have been identified. In other cases, transporters do not appear to be involved in drug uptake, and selectivity must lie with other parasite features, such as a specific target or activation of the drug. Lessons learned from studying the uptake of drugs currently in use may assist the design of a much needed new generation of trypanocides.