When an infected tsetse fly (top) bites a human it injects saliva that contains infectious trypanosomes into the skin. These parasites quickly transform into the “slender” form (blue), which can either go into the bloodstream or remain in the skin and nearby fat (i.e. the subcutaneous adipose). Once the trypanosomes become established in any of these tissues, they can transform into the “stumpy” form (orange) that can re-infect another tsetse fly (grey arrows). Transmission from fat to tsetse is plausible, but has not been demonstrated experimentally and is therefore labelled with a question mark. Parasite reservoirs might be less exposed to the immune system in skin or fat and may play an important role in transmitting sleeping sickness, and in maintaining the trypanosome infection in asymptomatic individuals.