A sedentary lifestyle is a major risk factor for cardiovascular disease, and rates of inactivity and cardiovascular disease are highly prevalent in our society. Cardiovascular disease is often associated with overactivity of the sympathetic nervous system, which has both direct and indirect effects on multiple organ systems. Although it has been known for some time that exercise positively affects the brain in terms of memory and cognition, only recently have changes in how the brain regulates the cardiovascular system been examined in terms of physical activity and inactivity. This brief review will discuss the evidence for physical activity-dependent neuroplasticity related to control of sympathetic outflow. It will focus particularly on recent studies from our laboratory and others that have examined changes that occur in the rostral ventrolateral medulla (RVLM), considered one of the primary brain regions involved in the regulation and generation of sympathetic nervous system activity.