Mechanical ventilation and positive end-expiratory pressure (PEEP) are considered to be the cornerstones of therapy for acute lung failure and acute respiratory distress syndrome (ARDS), when high levels of PEEP are applied in order to maintain or restore oxygenation, despite the fact that aggressive mechanical ventilation can markedly affect cardiac function in a complex and often unpredictable fashion. As heart rate usually does not change with PEEP, the entire fall in cardiac output is a consequence of a reduction in left ventricular stroke volume (LVSV). Therefore, changes in cardiac output caused by mechanical ventilation and PEEP are analyzed in terms of changes in SV and its determinants, i.e. preload, afterload, contractility and ventricular compliance. Mechanical ventilation with PEEP, like any other active or passive ventilatory maneuver, primarily affects cardiac function by changing lung volume and intrathoracic pressure (ITP). In order to describe the direct cardiocirculatory consequences of respiratory failure necessitating mechanical ventilation and PEEP, this review will focus on the effects of changes in lung volume, factors controlling venous return, the diastolic interactions between the ventricles and the effects of intrathoracic pressures on right and left ventricular function.