Human African trypanosomiasis (HAT) is responsible for around 3000 reported cases each year. Treatments for HAT are expensive and problematic to administer, and available drugs are old and less than ideal, some with high levels of toxicity that result in debilitating and, in some cases, fatal side effects. Treatment options are limited, with only one drug, eflornithine, introduced in the last 28 years. Here we examine the limitations of current chemotherapeutic approaches to manage HAT, the constraints to new drug development exploring drug failures and new drugs on the horizon, and consider the epidemiological, political, social, and economic factors influencing drug development. Drugs currently available for the treatment of HAT are unacceptable against a range of benchmarks. The ideal drug is a safe, oral compound with 95% efficacy against both stages of HAT, and a drug meeting these requirements could be used to prevent maternal transmission and prophylactically. Significant investment for the identification and development of drug candidates for HAT over the last decade has resulted in several promising drugs that are progressing through clinical development. However, a range of political and social barriers prevent clinical trials from being conducted effectively. An estimated 90% of cases occur in countries enduring conflict and political/social instability, which negatively impacts on health expenditure, infrastructure, and the ability to conduct clinical trials. During interepidemic periods, the few available HAT patients are thinly distributed, and while two promising new drugs are in the last stage of testing, the lack of patients available for recruitment into trials is problematic.