Slender cells proliferate in the mammalian bloodstream and produce SIF, triggering the density-dependent production of stumpy forms. This differentiation is inhibited by the action of signalling pathway(s) involving TbMAPK5 and ZFK. Once stumpy forms are generated, they are held poised for differentiation to procyclic forms by the action of TbPTP1 [25••]. These cells also express, at low level, a CCA receptor/transmitter for the signal to differentiate, which has access to the cell surface (shown as a ‘star’). Upon uptake by tsetse flies, Engstler and Boshart [16••] propose that a reduction in temperature of >15 °C promotes super-induction of the CCA receptor/transmitter that is trafficked to the stumpy cell surface, sensitising these cells to the inductive signal. Slender cells, in contrast, do not traffic the receptor/transmitter to the surface. Exposure to differentiation signals in the fly inactivates TbPTP1 and initiates transformation to procyclic forms, this being induced by CCA, proteolytic attack of the parasite surface or pH stress in the tsetse midgut and/or in vitro.