Cardiorespiratory fitness (CRF) is not only an objective measure of habitual physical activity, but also a useful diagnostic and prognostic health indicator for patients in clinical settings. Although compelling evidence has shown that CRF is a strong and independent predictor of all-cause and cardiovascular disease mortality, the importance of CRF is often overlooked from a clinical perspective compared with other risk factors such as hypertension, diabetes, smoking, or obesity. Several prospective studies indicate that CRF is at least as important as the traditional risk factors, and is often more strongly associated with mortality. In addition, previous studies report that CRF appears to attenuate the increased risk of death associated with obesity. Most individuals can improve their CRF through regular physical activity. Several biological mechanisms suggest that CRF improves insulin sensitivity, blood lipid profile, body composition, inflammation, and blood pressure. Based on the evidence, health professionals should encourage their patients to improve CRF through regular physical activity.