African sleeping sickness (or human African trypanosomiasis) is caused by unicellular eukaryotic parasites. These initially multiply in blood and lymph of infected hosts before infecting the cerebrospinal fluid, meninges, and circumventricular organs via the blood–cerebrospinal fluid barrier. During this stage of infection, the name-giving symptoms of sleeping sickness occur, that is, a deregulation of the sleep–wake cycle. In the further course of the disease, the parasite enters the brain parenchyma via the blood–brain barrier, causing encephalitis with a fatal outcome. Numerous publications on the development of human African trypanosomiasis usually disclaim to differentiate between the blood–brain barrier and the blood–cerebrospinal fluid barrier, although both are constructed differently and shield different compartments from the blood. Instead, the vague term of a general “brain infection” was often used. For clarification, we summarize the current knowledge about the pathogenesis of a cerebral trypanosomiasis and the significance of both respective barriers for progression of the disease. We describe how an in vitro blood–cerebrospinal fluid barrier can be used to investigate trypanosomal transmigration. Finally, we summarize how sleep–wake fragmentation may occur.