The beneficial effects of exercise on the cardiovascular system are well-accepted and provide an opportunity to identify new prevention and treatment strategies for cardiovascular disease (CVD) 1, 2. However, key knowledge gaps remain. Exercise represents a complex stimulus with varying impacts based on exercise type, duration, and intensity. Furthermore, exercise impacts multiple cell types and organs. Each of these factors needs to be considered in an attempt to harness the protective properties of exercise for the prevention of CVD in different patient groups. In this special issue, we have compiled mini-reviews from biomedical and clinical researchers worldwide, which explore mechanisms underlying the beneficial effects of exercise on the heart and prevention of CVD based on animal and human studies. The articles also cover i) the effects of exercise on the heart via tissue cross-talk, ii) the uncovering of potential signatures or biomarkers of cardiac health and cardiorespiratory fitness versus cardiac stress/dysfunction, and iii) opportunities of using exercise or approaches targeting key molecular mechanisms as a therapeutic approach to protect against CVD in settings such as obesity, heart failure, and even spaceflight.