Cardiopulmonary exercise testing adds measurement of ventilation and volume of oxygen uptake and exhaled carbon dioxide to routine physiological and performance parameters obtainable from conventional exercise testing, furnishing an all-around vision of the systems involved in both oxygen transport from air to mitochondria and its use during exercise. Peculiarities of cardiopulmonary exercise testing methodology are the use of ramp protocols and calibration procedures for flow meters and gas analyzers. Among the several parameters provided by this technique, peak oxygen uptake, first and second ventilatory thresholds, respiratory exchange ratio, oxygen pulse, slope of ventilation divided by exhaled carbon dioxide relationship, exercise oscillatory ventilation, circulatory power, and partial pressure of end-tidal carbon dioxide are among the most relevant in the clinical setting. The choice of parameters to be considered will depend on the indication to cardiopulmonary exercise testing in the individual subject or patient, namely, exercise tolerance assessment, prognostic stratification, training prescription, treatment efficacy evaluation, diagnosis of causes of unexplained exercise tolerance reduction, or exercise (patho)physiology evaluation for research purposes. Overall, cardiopulmonary exercise testing is a methodology now widely available and supported by sound scientific evidence. Despite this, its potential still remains largely underused. Strong efforts and future investigations are needed to address these issues and further promote the use of cardiopulmonary exercise testing in the clinical and research setting.