Trypanosomes inoculated by tsetse flies provoke human African trypanosomiasis (HAT), also called sleeping sickness. HAT exists in two forms: a chronic one caused by Trypanosoma brucei gambiense (g-HAT), in western/central Africa, and an acute form caused by T. b. rhodesiense (r-HAT), in eastern/southern Africa. HAT develops throughout two stages: (1) the haemolymphatic stage 1 comprising of irregular fever, chronic fatigue and lymphadenopathy; (2) the meningoencephalitic stage 2 with trypanosomes entering in brain comprises neurological signs, neuropsychiatric and sleep disorders. At the end of stage 2, a comatose state takes place prior to death. HAT diagnosis is based on serology and trypanosome search. A staging based on cerebrospinal fluid analysis may be performed. A dysregulation of cytokine networks and production is a HAT characteristic. Regarding nitric oxide (NO), trypanosomes deploy two main processes. In the periphery (1), they influence the competition between arginase/NO synthase (NOS) for their common substrate L-arginine; by inducing arginase, they favor polyamine production which is essential for their growth. They also decrease the trypanocidal NO production. In brain (2), an increase in the NO content has been evidenced together with the inducible NOS (iNOS) expression in glial cells. The enhanced brain NO production may protect against trypanosomes but also lead to the production of deleterious peroxynitrites. Four drugs administered parenterally have been employed: pentamidine and suramin for stage 1, and difluoromethylornithine (eflornithine) and melarsoprol for stage 2. All these drugs are endowed of toxicity. Moreover, to treat stage 2 g-HAT, nifurtimox can also be administered with eflornithine. Since 2018, however, fexinidazole, active orally in stage 1 and the early stage 2 of g-HAT, has greatly facilitated patient care. Preliminary results obtained with a single oral dose of acoziborole active on both stages are promising. Finally, for r-HAT stage 2, the toxic melarsoprol remains the only rescue.