A wide range of animal and human studies provide evidence for the potential of physical and cognitive exercise in promoting cognitive health later in life. The effects of such activities on intermediate outcomes, such as cognitive performance, are becoming clearer, as are the molecular mechanisms involved. Physical and cognitive exercise might increase "cognitive reserve" and increase the overall health of the brain, thereby reducing or delaying cognitive impairment and dementia. However, conclusive evidence for such benefits is not yet established. The third annual Bedside to Bench conference, cosponsored by The American Geriatrics Society and the National Institutes of Health's National Institute on Aging, reviewed current knowledge regarding the role of physical and cognitive exercise in promoting cognitive vitality. Conference attendees identified gaps in our current understanding of these processes and recommended next steps for research. In particular, researchers will need to explore clinical issues related to the timing, intensity, and duration of various types and combinations of physical and cognitive activities in animal models to elucidate the mechanisms involved and inform the design of future human studies. The concept of the enriched environment currently employed in animal studies to promote physical activity, socialization, and problem solving should be explored in human studies.