This manuscript, which arose from the inaugural Tom Rowland Lecture Series at the 2016 North American Society for Pediatric Exercise Medicine conference, provides a brief descriptive review of what is known (i.e., the state of the science) regarding the relation of childhood physical activity (PA) and cardiorespiratory fitness (CRF) to brain health, cognition, and academic outcomes. Gaps in the knowledgebase are identified, including characteristics of the PA stimulus that promotes changes in brain and cognition, whether critical periods in development exist in which PA/CRF may have a disproportionately large influence, the understanding of individual difference factors, and the influence upon learning. Lastly, several possible directions for future research are proposed. Although the field of childhood PA, CRF, brain, and cognition is rapidly expanding, there is considerable room for future growth. This manuscript may be helpful in shaping that future growth, with the goal of improving lifelong health and effective functioning.