Weaning from mechanical ventilation can represent a significant period of time during ICU stay. However, the removal of the endotracheal tube may trigger or exacerbate the patient’s respiratory effort due to several factors. Clinicians should be aware of these factors in advance to minimize the occurrence of weaning failure. The factors can be divided into those related to the airway, such as upper airway obstruction or difficulty protecting the upper airway, and those related to gas exchange alterations, muscle pump insufficiency, and extrapulmonary causes. Several measurements are available to assess the risk of extubation failure, such as spontaneous breathing test (SBT), cuff leak test, mechanical ventilation measurements (P0.1 and ΔPocc), and, more recently, variables obtained by electrical impedance tomography (end-expiratory lung impedance and gradient index). Thus, the spectrum of causes of extubation failure should be identified and treated promptly. Systematic protocols should be used to assess risk factors, prepare and correctly apply the SBT, and evaluate post-extubation care with rapid reintubation in the event of failure.