Weaning failure, defined as failure to pass a spontaneous breathing trial (SBT) or need of reintubation within 48 hours after extubation, involves up to 40% of critically ill intubated patients and is associated with increased morbidity and mortality. The pathophysiology of difficult weaning is complex. Although the most common cause is respiratory failure, cardiovascular dysfunction is increasingly recognized as a frequent cause of weaning failure. The abrupt transition from positive pressure ventilation to spontaneous breathing challenges the cardiovascular system through various mechanisms, mainly by increasing biventricular preload and left ventricular afterload. In high-risk patients, including those with previous (known or unknown) cardiovascular or pulmonary disease, these pathophysiological changes can lead to weaning-induced cardiac failure. Knowledge of this complex pathophysiology is fundamental to suspect weaning-induced cardiac failure. In this case, a diagnostic workup should be promptly obtained to confirm the diagnosis, in order to develop a correct treatment strategy. Since non-invasive ventilation (NIV) provides positive pressure ventilatory support avoiding many of the risks associated with invasive ventilation, it has been proposed as a strategy to facilitate ventilatory weaning. In this setting, it has been demonstrated that NIV should be considered in selected patients as an alternative weaning strategy (with the objective of shortening the duration of mechanical ventilation) or as a prophylactic measure to prevent acute respiratory and/or cardiovascular failure after extubation. Of note, immediate initiation of NIV after extubation and careful patient selection are key factors to the achievement of these objectives. In contrast, treatment of established post-extubation acute respiratory failure with NIV is not recommended.