In this issue of Blood, Brothers et al demonstrate that voxelotor lowers brain blood flow and oxygen extraction fraction (OEF) in children with sickle cell disease. 1 Sickle cell disease causes both large and small blood vessels in the brain to remodel, leading to both overt and silent stroke. The baseline brain hemodynamic state in chronic anemias can be characterized by increased blood flow, decreased vascular flow reserve, 2 normal to decreased whole brain OEF, 3 and severely hypoxic deep white matter structures. 3,4 Silent strokes and volume loss accumulate in the deep white matter, with concordant neurocognitive consequences.