Clinical and experimental evidence indicate that physical activity has a positive impact on brain function; however, the molecular bases for how exercise affects the structure and function of the brain are largely unknown. We have investigated the influences of variable periods of voluntary wheel-running on the expression of basic fibroblast growth factor and its mRNA in various brain regions. Nuclease protection assays revealed that the hippocampus was the only region examined exhibiting changes in FGF-2 mRNA as a result of exercise. FGF-2 mRNA increased to reach a peak by the 4th night of wheel-running. FGF-2 immunoreactivity, normally located in the perinuclear area of astrocytes, following exercise became stronger and appeared to spread to the cytoplasm and processes of astrocytes. Quantification of the FGF-2-immunoreactive astrocytes showed an increase in density between 2 and 4 nights of running in discrete regions of the hippocampus. These results demonstrate that exercise regulates FGF-2 expression and suggest that growth factors are likely mediators of the positive effects of exercise on the brain.