Research exploring illness experiences of young people with sickle cell disease (SCD) has, to date, ignored fatigue, despite the distinctive anaemic nature of SCD. To examine adolescents with SCD fatigue experiences, we conducted narrative and picture-elicitation interviews with 24 adolescents in Ghana. A grounded theory, ‘body as a machine’ was constructed from the data. Fatigue represented the most restrictive and disruptive aspect of growing up with SCD. Its meaning and significance laid in what it symbolised. Fatigue represented a socially undesirable feature that was stigmatising, due to the expectations of high physicality in adolescence. Fatigue was therefore a major threat to normalcy. The social significance of the physical body and its capacities shaped the adolescents’ fatigue experiences. Managing fatigue to construct/maintain socially acceptable identities dominated the adolescents’ lives. Consequently, there is a need for a recognition of the significance of fatigue to adequately support young people growing up with SCD.