Non-invasive ventilation (NIV) is increasingly used in patients with acute respiratory failure, but few data exist regarding current sedation practices during NIV. Mask intolerance or claustrophobia, and delirium and agitation, may lead to NIV failure, requiring endotracheal intubation. Judicious use of sedation during NIV could be one of the valuable options for some of these patients at risk of intubation. Although different sedatives have been used in published studies, the objectives of sedation are similar: allowing mitigation of patient discomfort and obtaining the desired level of sedation. Whatever the sedative used, the goal is to achieve sedation to a point where the patients are awake and arousable and comfortable. Pilot studies suggest that continuous infusion of a single sedative agent may decrease patient discomfort, with no significant effects on respiratory drive, respiratory pattern, or hemodynamics. In addition, gas exchange improved under NIV with sedation. While the current limited data available suggests that sedation during NIV is safe and feasible, more widespread application should await the results of randomized clinical trials.