BACKGROUND: Holistic approaches to neuropsychological rehabilitation have progressively been recognized as an important form of rehabilitative care for persons who have a history of moderate to severe traumatic brain injury. OBJECTIVE: After providing historical and contemporary perspectives, identify challenges and opportunities facing the field of neuropsychological rehabilitation. METHODS: Selective literature review from neuropsychological rehabilitation, neurosciences, learning theory, cognitive neuropsychology, and psychotherapy that highlight challenges to the development of holistic neuropsychological rehabilitation. RESULTS: Ten challenges and associated opportunities that face the field of holistic neuropsychological rehabilitation are identified. Illustrations of these challenges and opportunities are provided. CONCLUSIONS: Effectively addressing the challenges that face holistic neuropsychological rehabilitation will result in greater advances for this field of care for both children and adults.