© The Author(s) 2018. There is a proliferation of research examining the effects of exercise on mobility and cognition in the general population and those with neurological disorders as well as focal research examining possible neural mechanisms of such effects. However, there is seemingly a lack of focus on what it is about exercise, in particular, that drives adaptive central nervous system neuroplasticity. We propose a novel conceptual framework (ie, PRIMERS) that describes such adaptations as occurring via activity-dependent neuroplasticity based on the integrative processing of multisensory input and associated complex motor output that is required for the regulation of physiological systems during exercise behavior. This conceptual framework sets the stage for the systematic examination of the effects of exercise on brain connectivity, brain structure, and molecular/cellular mechanisms that explain improvements in mobility and cognition in the general population and persons with multiple sclerosis (MS). We argue that exercise can be viewed as an integrative, systems-wide stimulus for neurorehabilitation because impaired mobility and cognition are common and co-occurring in MS.