For over 50 years it has been known that there are considerable differences in the severity and rate of progression of both Trypanosoma brucei rhodesiense and T. b. gambiense infection between individuals. Yet research into the factors, whether parasite or host, which control virulence in Human African trypanosomiasis is in its infancy. In this paper we review the clinical evidence for virulence variation and the epidemiological and experimental data that give clues as to the mechanisms involved. Evidence will be presented for both asymptomatic forms of T. b. gambiense infection and low virulence forms of T. b. rhodesiense infection in humans. While in both cases the mechanisms remain to be elucidated, the overall infection virulence phenotype is determined by both parasite and host genotype.