Exercise can have profound effects on numerous biologic systems within the human body, including the central nervous system (CNS). The inherent complexity of the CNS, and the methodologic difficulties in evaluating its in vivo neurochemistry in humans, provide challenges to investigators studying the impact of exercise on the CNS. As a result, our knowledge in this area of exercise science remains relatively limited. However, advances in research technology are allowing investigators to gain valuable insight into the neurobiologic mechanisms that contribute to the bidirectional communication that occurs between the periphery and the CNS during exercise. This article examines how exercise-induced alterations in the CNS contribute to central fatigue and the overtraining syndrome, and how exercise can influence psychologic wellbeing and cognitive function.