Mechanical ventilation incurs substantial morbidity, mortality, and costs. Both premature extubation and delayed extubation can cause harm. Therefore, weaning that is both expeditious and safe is highly desirable. The purpose of this review is to summarize the literature related to weaning modes, spontaneous breathing trials, weaning predictors, weaning with noninvasive positive pressure ventilation, and weaning protocols. We used 5 computerized databases and a duplicate independent review process to select articles for this review. We included randomized clinical trials evaluating any weaning interventions and nonrandomized trials of weaning predictors, with a focus on studies reporting clinically important outcomes. We abstracted quantitative data using several metrics and pooled results across studies only when our assessment of the patients, interventions, and outcomes indicated that pooling was legitimate. The available clinical research evidence suggests that, for progressive weaning of the level of mechanical support, it may be best to choose modes other than synchronized intermittent mandatory ventilation and it is unreasonable to be dogmatic about the use of other modes. There may also be substantial benefits to early extubation with back-up institution of noninvasive positive pressure ventilation, as needed, though this remains an experimental approach. For trials of spontaneous breathing, low levels of pressure support may hasten extubation. We did not uncover any consistently powerful weaning predictors, suggesting that formal use of predictors in patients being considered for reduction or discontinuation of mechanical support is unlikely to improve patient care. The likely explanation is that clinicians already fully consider information from weaning predictors in choosing patients for trials of reduction or discontinuation of mechanical ventilation. Finally, implementation of respiratory therapist- or nurse-driven protocols may be useful for all phases of weaning, and clinicians should adopt daily assessment for a trial of unassisted breathing as a safe method to reduce the duration of mechanical ventilation.