Cardiopulmonary exercise testing (CPET) is under-utilized in assessing patients with prominent complaints of dyspnea or exercise limitation and should be one of the early tests used to assess exercise intolerance. The standard 12-lead ECG treadmill stress test focuses on coronary artery disease and is inadequate to assess the various subsystems (i.e., heart, lung, pulmonary vascular, peripheral vascular, muscle and psychological motivation) that can contribute individually, or more commonly in an interrelated fashion, to cause exercise limitation. The additional gas exchange information from CPET is very helpful in the identification of a more precise diagnosis, assessment of the severity of the impairment, determination of response to treatment and prediction of mortality. This special report will highlight some of the recent important applications of CPET to clinical medicine with specific references to heart failure, preoperative risk assessment, and regenerative and rehabilitative medicine, and the evidence that currently exists in the medical literature to support routine CPET use. It will also detail the recent evidence regarding the association of VO2max and survival in health and disease.