For most mechanically ventilated patients, weaning can be accomplished quickly and easily. However, there is a smaller group of ventilated patients who fail to wean and remain ventilator-dependent. These patients account for a significant amount of health care costs and pose a great challenge for clinicians. Detailed knowledge of the etiology and pathophysiology of weaning failure is very important for the "treatment" of difficult to wean patients, and is thoroughly presented in this article. Based on this physiological background, strategies and techniques are proposed that are useful for the gradual transition to spontaneous ventilation.