Resumption of spontaneous unassisted breathing after an episode of acute respiratory failure often is achieved without major difficulty. In a significant number of patients however, weaning from mechanical ventilation is a long and difficult process that markedly increases the duration of mechanical ventilation and consumes a significant fraction of critical care resources. Some criteria have been suggested to predict early and more accurately the moment the patient is ready to be separated from the ventilator. At the present time, the f/VT ratio (rapid shallow breathing index) appears to yield the best predictive power. None of these indices, however, is powerful enough to be relied on solely, and their use should be limited to that of aids to the critical care physician. The inability to sustain spontaneous ventilation usually is the consequence of an imbalance between respiratory demand and respiratory muscle capacity. Increased elastic workload, increased resistive workload, and increased VE are the main causes of excessive demand imposed on the respiratory system. Respiratory muscle pump failure usually relates to peripheral nerve dysfunction or muscular dysfunction. Left ventricular dysfunction also is an important cause of weaning failure. The usual methods of weaning from mechanical ventilation are T-piece trials with abrupt definitive discontinuation of mechanical ventilation if tolerated or with progressive intermittent trials, IMV, and PSV. All have their advantages and disadvantages, and the method of weaning per sé is not the only critical factor. Although their conclusions were different regarding the best method of weaning, however, two recent clinical trials suggest that ventilatory management has a major influence on the outcome of weaning from mechanical ventilation in difficult-to-wean patients. The global management of such patients requires a systematic approach with consideration of all factors involved in the process of separation from the ventilator. New computer-assisted systems already are tested and, in the future, may provide a significant advantage in the management of weaning from mechanical ventilation.