This commentary reviews selected biomedical and clinical research examining the relationship between physical exercise and cognitive function especially in youth with disability. Youth with physical disability may not benefit from the effects of exercise on cardiovascular fitness and brain health since they are less active than their non-disabled peers. In animal models, physical activity enhances memory and learning, promotes neurogenesis and protects the nervous system from injury and neurodegenerative disease. Neurotrophins, endogenous proteins that support brain plasticity likely mediate the beneficial effects of exercise on the brain. In clinical studies, exercise increases brain volume in areas implicated in executive processing, improves cognition in children with cerebral palsy and enhances phonemic skill in school children with reading difficulty. Studies examining the intensity of exercise required to optimize neurotrophins suggest that moderation is important. Sustained increases in neurotrophin levels occur with prolonged low intensity exercise, while higher intensity exercise, in a rat model of brain injury, elevates the stress hormone, corticosterone. Clearly, moderate physical activity is important for youth whose brains are highly plastic and perhaps even more critical for young people with physical disability.