This chapter discusses respiratory system mechanics and gas exchange during anesthesia of morbidly obese (MO) patients. It describes ventilatory strategies that can improve oxygenation while protecting the lungs from ventilator-induced mechanical stress. After induction of anesthesia, deterioration of partial pressure of arterial oxygen (PaO2) occurs in MO patients. For normal weight and obese patients, prolonged mechanical ventilation with high pressure can induce mechanical stress and acute ventilator-associated lung injury (VALI). PaCO2 is correlated with effective ventilation, and an acute decrease in PaCO2 after recruitment indicates improvement (decrease) of physiologic dead space. The chapter summarizes various peri-operative strategies that provide open-lung ventilation and protect against ventilator-induced lung injury. High tidal volume (VT) without positive end-expiratory pressure (PEEP) during mechanical ventilation may cause subclinical lung injury. For MO patients, a protective ventilatory strategy incorporates prevention of atelectasis and lung overexpansion while using lower end-inspiratory pressure (PEI).