Positive pressure ventilation (PPV) is often required in critically ill patients with unstable cardiovascular status. Mechanical ventilation can result in further alterations of cardiac output (CO) and arterial blood pressure. The evidence supporting a variety of potential pathophysiologic mechanisms for hemodynamic instability related to PPV is examined. The predominant determinant of hypotension during mechanical ventilation appears to be a reduction in preload. The impaired preload is due to the smaller gradient for venous return caused by the increased intrathoracic pressure. Additional potential pathophysiologic effects of PPV include increased pulmonary vascular resistance, ventricular interdependence, changes in contractility, and altered humoral and autonomic responses. A number of clinical scenarios such as acute respiratory distress syndrome, obstructive airway disease, and heart failure, which commonly require mechanical ventilation, are examined in further detail.