Accumulating evidence finds that exercise can improve brain function and delay or prevent the onset of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. While the underlying mechanisms remain unclear, recent research suggests that exercise-induced activation of peripheral systems such as muscle, gut, liver, and adipose tissue may affect neural plasticity. A special issue of Brain Plasticity presents new research and insights on neural plasticity and the role of peripheral factors in cognitive health.