Resistance to African trypanosomes in humans relies on targeting of a trypanosome lytic factor 1 (TLF1) to trypanosome haptoglobin-hemoglobin receptor (HpHbR). While TLF1 avoidance by the inactivation of the HpHbR contributes to Trypanosoma brucei gambiense human infectivity, the evolutionary trade-off of this adaptation is unknown. Both T. b. gambiense with inactive HpHbR, as well as a genetically engineered T.b.brucei HpHbR knock-out show only trace levels of intracellular heme and lack the downstream hemoprotein activities, thereby providing an extraordinary example of aerobic parasite proliferation in the absence of heme. We further show that HpHbR facilitates the developmental progression by inducing PAD-1 expression that is associated with the formation of cell cycle-arrested stumpy forms in T. b.brucei . Accordingly, T. b. gambiense was found to be poorly competent for slender-to-stumpy differentiation unless a functional HpHbR receptor derived from T. b. brucei was genetically restored.