The cardiac benefits of exercise have been recognized for centuries. Studies have undisputedly shown that regular exercise is beneficial for the cardiovascular system in young, old, healthy and diseased populations. For these reasons, physical activity has been recommended worldwide for cardiovascular disease prevention and treatment. Although the benefits of exercise are clear, understanding of the molecular triggers that orchestrate these effects remains incomplete and has been a topic of intense research in recent years. Here, we provide a comprehensive review of the cardiac effects of physical activity, beginning with a brief history of exercise in cardiovascular medicine and then discussing seminal work on the physiological effects of exercise in healthy, diseased and aged hearts. Later, we revisit pioneering work on the molecular mechanisms underlying the cardiac benefits of exercise, and we conclude with our view on the translational potential of this knowledge as a powerful platform for cardiovascular disease drug discovery.