Trypanosome lytic factors (TLFs) are high-density lipoproteins and components of primate innate immunity. TLFs are characterized by their ability to kill extracellular protozoon parasites of the genus Trypanosoma. Two subspecies of Trypanosoma brucei have evolved resistance to TLFs and can consequently infect humans, resulting in the disease African sleeping sickness. The unique protein components of TLFs are a hemoglobin-binding protein, haptoglobin-related protein and a pore-forming protein, apoL-I. The recent advances in our understanding of the roles that these proteins play in the mechanism of TLF-mediated lysis are highlighted in this article. In light of recent data, which demonstrate that TLFs can ameliorate infection by the intracellular pathogen Leishmania, we also discuss the broader function of TLFs as components of innate immunity.