Arsenical monotherapies were previously very successful for treating human African trypanosomiasis (HAT). Melarsoprol resistance emerged as early as the 1970s and was widespread by the late 1990s. Melarsoprol resistance represents the only example of widespread drug resistance in HAT patients where the genetic mechanism has been established. The current goal of elimination of HAT as a public health problem by 2020 may be undermined by the emergence and spread of resistance to current or new drugs. Insights into potential resistance mechanisms for current and new drugs will facilitate predictions of the likelihood of resistance and will also facilitate rational approaches to minimizing, monitoring, and tackling the future emergence of resistance.