Abstract Exercise intolerance is a prominent feature of several cardiovascular conditions. However, the physical effort requires the intertwined adaptation of several factors, namely the cardiovascular system, the lungs, and peripheral muscles. Several abnormalities in each domain may be present in a given patient. Cardiopulmonary exercise testing (CPET) has been used to investigate metabolic and ventilatory alterations responsible for exercise intolerance but does not allow for direct evaluation of cardiovascular function. However, this can readily be obtained by concomitant exercise-stress echocardiography (ESE). The combined CPET-ESE approach allows for precise and thorough phenotyping of the pathophysiologic mechanisms underpinning exercise intolerance. Thus, it can be used to refine the diagnostic workup of patients with dyspnoea of unknown origin, as well as improve risk stratification and potentially guide the therapeutic approach in specific conditions, including left and right heart failure or valvular heart disease. However, given its hitherto sporadic use, both the conceptual and technical aspects of CPET-ESE are often poorly known by the clinician. Improving knowledge in this field could significantly aid in anticipating individual disease trajectories and tailoring treatment strategies accordingly. Therefore, we designed this review to revise the pathophysiologic correlates of exercise intolerance, the practical principles of the combined CPET-ESE examination, and its main applications according to current literature.