Transpulmonary pressure is an essential physiologic concept as it reflects the true pressure across the alveoli, and is a more precise marker for lung stress. To calculate transpulmonary pressure, one needs an estimate of both alveolar pressure and pleural pressure. Airway pressure during conditions of no flow is the most widely accepted surrogate for alveolar pressure, while esophageal pressure remains the most widely measured surrogate marker for pleural pressure. This review will cover important concepts and clinical applications for esophageal manometry, with a particular focus on how to use the information from esophageal manometry to adjust or titrate ventilator support. The most widely used method for measuring esophageal pressure uses an esophageal balloon catheter, although these measurements can be affected by the volume of air in the balloon. Therefore, when using balloon catheters, it is important to calibrate the balloon to ensure the most appropriate volume of air, and we discuss several methods which have been proposed for balloon calibration. In addition, esophageal balloon catheters only estimate the pleural pressure over a certain area within the thoracic cavity, which has resulted in a debate regarding how to interpret these measurements. We discuss both direct and elastance-based methods to estimate transpulmonary pressure, and how they may be applied for clinical practice. Finally, we discuss a number of applications for esophageal manometry and review many of the clinical studies published to date which have used esophageal pressure. These include the use of esophageal pressure to assess lung and chest wall compliance individually which can provide individualized information for patients with acute respiratory failure in terms of setting PEEP, or limiting inspiratory pressure. In addition, esophageal pressure has been used to estimate effort of breathing which has application for ventilator weaning, detection of upper airway obstruction after extubation, and detection of patient and mechanical ventilator asynchrony.