Optimizing patient-ventilator synchrony is essential in managing patients who require prolonged mechanical ventilation in the long-term acute-care hospital. Inadequate synchrony can increase work of breathing, cause patient discomfort, and delay both weaning and general rehabilitation. Achieving optimal synchrony in the long-term acute-care hospital depends on a number of factors, including adjusting ventilator settings in response to improving lung function; adjusting psychotropic medications to control delirium, anxiety, and depression; and ensuring there is a well positioned correctly sized tracheostomy tube in the airway. The purpose of this review is to provide an update on issues pertinent to patient-ventilator synchrony in the LTACH setting.