Trypanosoma brucei brucei is noninfectious to humans because of its sensitivity to the cytolytic activity of normal human serum. Biochemical evidence indicates that the active component of human serum is high-density lipoprotein (HDL). Several possible mechanisms have been proposed for the killing of trypanosomes by human HDL, and while a unified model that accounts for all experimental information is lacking, there is substantial evidence that receptor-mediated binding and endocytosis might be required for lysis. Trypanosomes resistant to the lytic effects of human HDL cause human sleeping sickness. The basis for the resistance of these parasites to HDL-mediated killing is unknown. The sensitivity of T. brucei brucei to the cytolytic action of human HDL is developmentally regulated and resistance correlates with life-cycle specific changes in macromolecular uptake by the organism.