Weaning the patient from mechanical ventilation is a major challenge for the intensivist. "Wean" means to separate gradually. The term "Liberation" is a better term since the patients can be more quickly removed from the ventilator based on their clinical conditions. In this review article, the initial required criteria to start and weaning methods from mechanical ventilation were evaluated based on various studies; and at the end, the protocol for separation of mechanical ventilation is recommended. Studies showed that prolonged mechanical ventilation is associated with ventilator-associated complications such as pneumonia, ventilator-induced lung injury and increased mortality. Making premature or delayed decision in weaning the patient from the ventilator increases the mortality rate. Studies also showed that using clinical parameters for weaning the patient from the ventilator is better than clinical judgments alone. Duration of weaning from the ventilator must be more than 40% of the duration of full support ventilation. The method of SIMV is not suitable for weaning from the ventilator, while spontaneous breathing test is more suitable. After improving oxygenation, first Fio2, PEEP, and then respiratory rate are reduced. Weaning from the ventilator starts early in the morning. The infusion of sedating medications should be discontinued and, if necessary, administered by bolus infusion. In case of intolerance, weaning from the ventilator will be postponed to 24 hours later.