The development of a pronounced iliotibial band (ITB) is an anatomically distinct evolution of humans. The mechanical behaviour of this “new” structure is still poorly understood and hotly debated in current literature. Iliotibial band syndrome (ITBS) is one of the leading causes of lateral knee pain injuries in runners. We currently lack a comprehensive understanding of the healthy behaviour of the ITB, and this is necessary prior to further investigating the aetiology of pathologies like ITBS. Therefore, the purpose of this narrative review was to collate the anatomical, biomechanical and clinical literature to understand how the mechanical function of the ITB is influenced by anatomical variation, posture and muscle activation. The complexity of understanding the mechanical function of the ITB is due, in part, to the presence of its two in-series muscles: gluteus maximus (GMAX) and tensor fascia latae (TFL). At present, we lack a fundamental understanding of how GMAX and TFL transmit force through the ITB and what mechanical role the ITB plays for movements like walking or running. While there is a range of proposed ITBS treatment strategies, robust evidence for effective treatments is still lacking. Interventions that directly target the running biomechanics suspected to increase either ITB strain or compression of lateral knee structures may have promise, but clinical randomised controlled trials are still required.