Human African trypanosomiasis or sleeping sickness is caused by infection with two subspecies of the tsetse-fly-vectored haemoflagellate parasite Trypanosoma brucei. Historically, epidemic sleeping sickness has caused massive loss of life, and related animal diseases have had a crucial impact on development in sub-Saharan Africa. After a period of moderately successful control during the mid-part of the 20th century, sleeping sickness incidence is currently rising, and control is hampered by a combination of factors, including civil unrest and the possible development of drug resistance by the parasites. The prevailing view is that the disease is invariably fatal without anti-trypanosomal drug treatment. However, there have also been intriguing reports of wide variations in disease severity as well as evidence of asymptomatic carriers of trypanosomes. These differences in the presentation of the disease will be discussed in the context of our knowledge of the immunology of trypanosomiasis. The impact of dysregulated inflammatory responses in both systemic and CNS pathology will be examined and the potential for host genotype variation in disease severity and control will be discussed.