Children with acute hypoxic-ischaemic events (e.g. stroke) and chronic neurological conditions associated with hypoxia frequently present to paediatric neurologists. Failure to adapt to hypoxia may be a common pathophysiological pathway linking a number of other conditions of childhood with cognitive deficit. There is evidence that congenital cardiac disease, asthma and sleep disordered breathing, for example, are associated with cognitive deficit, but little is known about the mechanism and whether there is any structural change. This review describes what is known about how the brain reacts and adapts to hypoxia, focusing on epilepsy and sickle cell disease (SCD). We prospectively recorded overnight oxyhaemoglobin saturation (SpO[subscript 2]) in 18 children with intractable epilepsy, six of whom were currently or recently in minor status (MS). Children with MS were more likely to have an abnormal sleep study defined as either mean baseline SpO[subscript 2] less than 94% or greater than 4 dips of greater than 4% in SpO[subscript 2]/hour (p = 0.04). In our series of prospectively followed patients with SCD who subsequently developed acute neurological symptoms and signs, mean overnight SpO[subscript 2] was lower in those with cerebrovascular disease on magnetic resonance angiography (Mann-Whitney, p = 0.01). Acute, intermittent and chronic hypoxia may have detrimental effects on the brain, the clinical manifestations perhaps depending on rapidity of presentation and prior exposure.