When Ayres first presented the theory of sensory integration (SI), she grounded it in the neuroscience literature. Neuroplasticity was then, and is today, considered to be at the heart of this theory. This evidence-based review sought to critically examine the basic science literature to specifically identify evidence for the assumptions and tenets of Ayres’ theory of SI. We reviewed literature between 1964 and 2005, within psychological, physiological, and biomedical areas, addressing neuroplasticity. The review focused on sensorimotor-based neuroplasticity; explored the data that addressed the links among sensory input, brain function, and behavior; and evaluated its relevance in terms of supporting or refuting the theoretical premise of occupational therapy using an SI framework (OT/SI) to treatment. Although direct application from basic science to OT/SI is not feasible, we concluded that there was a basis for the assumptions of Ayes’ SI theory.