African trypanosomes are responsible for sleeping sickness in man and nagana in cattle, which are both tremendous health burdens in Africa. Most African trypanosome species are killed by human serum. This is due to a serum trypanolytic particle specific of some old world monkeys and great apes, an HDL subclass containing two proteins which appeared recently in mammalian evolution, apolipoprotein L1 and haptoglobin related protein. Nevertheless, two African trypanosome species, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are able to infect humans, because they developed resistance to trypanolysis. Resistance to human serum in Trypanosoma brucei rhodesiense is due to a single gene called SRA. This mechanism of lysis-resistance is therefore an example of a natural drug-antidote system which evolved during a pathogen-host arms race. The lysis and resistance mechanisms, their molecular components as well as their mode of action are reviewed. I also discuss how components of the system would be suitable drug targets and how the system could be engineered to generate an effective synthetic drug.