Skillfully implemented mechanical ventilation (MV) may prove of immense benefit in restoring physiologic homeostasis. However, since hemodynamic instability is a primary factor influencing mortality in acute respiratory distress syndrome (ARDS), clinicians should be vigilant regarding the potentially deleterious effects of MV on right ventricular (RV) function and pulmonary vascular mechanics (PVM). During both spontaneous and positive pressure MV (PPMV), tidal changes in pleural pressure (PPL), transpulmonary pressure (PTP, the difference between alveolar pressure and PPL), and lung volume influence key components of hemodynamics: preload, afterload, heart rate, and myocardial contractility. Acute cor pulmonale (ACP), which occurs in 20–25% of ARDS cases, emerges from negative effects of lung pathology and inappropriate changes in PPL and PTP on the pulmonary microcirculation during PPMV. Functional, minimally invasive hemodynamic monitoring for tracking cardiac performance and output adequacy is integral to effective care. In this review we describe a physiology-based approach to the management of hemodynamics in the setting of ARDS: avoiding excessive cardiac demand, regulating fluid balance, optimizing heart rate, and keeping focus on the pulmonary circuit as cornerstones of effective hemodynamic management for patients in all forms of respiratory failure.