Recent data show an alarming increasing trend in obesity around the world. Mechanical ventilation in this population requires specific ventilatory settings due to the mechanical and inflammatory alterations observed in obesity. In this line, end-expiratory lung volume is decreased, leading to impairment in the mechanics of the respiratory system, lung and chest wall as well as gas-exchange. Furthermore, the inflammatory process acts on distal airways, increasing airway responsiveness, or on pulmonary endothelium cells, increasing the molecules related to the adherence of inflammatory cells. In order to reduce lung stress and strain, as well as minimize the risk of ventilator associated lung injury, mechanical ventilation management should be conducted with the following strategies: 1) stepwise recruitment maneuver before positive end-expiratory pressure application, which requires titration according to respiratory system dynamic compliance; and 2) tidal volume (VT) titration according to inspiratory capacity. In summary, the overall objective is to ensure an adequate setting of ventilator parameters in order to minimize the inflammatory impact already present in obese patients as well as prevent further lung damage.