Regular exercise broadly enhances physical and mental health throughout the lifespan. Animal models have provided us with the tools to gain a better understanding of the underlying biochemical, physiological, and morphological mechanisms through which exercise exerts its beneficial cognitive effects. One brain region in particular, the hippocampus, is especially responsive to exercise. It is critically involved in learning and memory and is one of two regions in the mammalian brain that continues to generate new neurons throughout life. Exercise prevents the decline of the hippocampus from aging and ameliorates many neurodegenerative diseases, in part by increasing adult hippocampal neurogenesis but also by activating a multitude of molecular mechanisms that promote brain health. In this chapter, we first describe some rodent models used to study effects of exercise on the brain. Then we review the rodent work focusing on the mechanisms behind which exercise improves cognition and brain health in both the normal and the diseased brain, with emphasis on the hippocampus.