Periodic breathing during incremental cardiopulmonary exercise testing is a regularly recurring waxing and waning of tidal volume due to oscillations in central respiratory drive. Periodic breathing is a sign of respiratory control system instability, which may occur at rest or during exercise. The possible mechanisms responsible for exertional periodic breathing might be related to any instability of the ventilatory regulation caused by: (1) increased circulatory delay (i.e., circulation time from the lung to the brain and chemoreceptors due to reduced cardiac index leading to delay in information transfer), (2) increase in controller gain (i.e., increased central and peripheral chemoreceptor sensitivity to arterial partial pressure of oxygen and of carbon dioxide), or (3) reduction in system damping (i.e., baroreflex impairment). Periodic breathing during exercise is observed in several cardiovascular disease populations, but it is a particularly frequent phenomenon in heart failure due to systolic dysfunction. The detection of exertional periodic breathing is linked to outcome and heralds worse prognosis in heart failure, independently of the criteria adopted for its definition. In small heart failure cohorts, exertional periodic breathing has been abolished with several dedicated interventions, but results have not yet been confirmed. Accordingly, further studies are needed to define the role of visceral feedbacks in determining periodic breathing during exercise as well as to look for specific tools for preventing/treating its occurrence in heart failure.