Humans have developed a particular innate immunity system against African trypanosomes, and only two Trypanosoma brucei clones (T. b. gambiense, T. b. rhodesiense) can resist this defence and cause sleeping sickness. The main players of this immunity are the primate-specific apolipoprotein L-I (apoL1) and haptoglobin-related protein (Hpr). These proteins are both associated with two serum complexes, a minor subfraction of HDLs and an IgM/apolipoprotein A-I (apoA1) complex, respectively, termed trypanosome lytic factor (TLF) 1 and TLF2. Although the two complexes appear to lyse trypanosomes by the same mechanism, they enter the parasite through various modes of uptake. In case of TLF1 one uptake process was characterized. When released in the circulation, haemoglobin (Hb) binds to Hpr, hence to TLF1. In turn the TLF1-Hpr-Hb complex binds to the trypanosome haptoglobin (Hp)-Hb receptor, whose original function is to ensure haem uptake for optimal growth of the parasite. This binding triggers efficient uptake of TLF1 and subsequent trypanosome lysis. While Hpr is involved as TLF ligand, the lytic activity is due to apoL1, a Bcl-2-like pore-forming protein. We discuss the in vivo relevance of this uptake pathway in the context of other potentially redundant delivery routes.