Weaning failure has been defined as failure to discontinue mechanical ventilation, as assessed by the spontaneous breathing trial, or need for re-intubation after extubation, so-called extubation failure. Both events represent major clinical and economic burdens, and are associated with high morbidity and mortality. The most important mechanism leading to discontinuation failure is an unfavourable balance between respiratory muscle capacity and the load they must face. Beyond specific diseases leading to loss of muscle force-generating capacity, other factors may impair respiratory muscle function, including prolonged mechanical ventilation, sedation, and ICU-acquired neuromuscular dysfunction, potentially consequent to multiple factors. The load depends on the mechanical properties of the respiratory system. An increased load is consequent to any condition leading to increased resistance, reduced compliance, and/or occurrence of intrinsic positive-end-expiratory pressure. Noteworthy, the load can significantly increase throughout the spontaneous breathing trial. Cardiac, cerebral, and neuropsychiatric disorders are also causes of discontinuation failure. Extubation failure may depend, on the one hand, on a deteriorated force-load balance occurring after removal of the endotracheal tube and, on the other hand, on specific problems. Careful patient evaluation, avoidance and treatment of all the potential determinants of failure are crucial to achieve successful discontinuation and extubation.