Discontinuation from mechanical ventilation is one of the most frequently performed interventions in the critical care setting. Diverse underlying conditions or complications occurring during the period of mechanical ventilation can lead to weaning failure. After the different relatively common causes of failure to wean have been ruled out, a neurologic disorder should be excluded. In this case, the differential diagnoses must include critical illness polyneuropathy (CIP), neuromuscular junction defects, and myopathies. CIP is the most strictly defined neuromuscular complication in critically ill patients, which becomes manifest by a failure to wean from mechanical ventilation. In fact, it was originally described in patients with difficult weaning from ventilatory support. Various studies have attempted to determine if CIP prolongs the duration of mechanical ventilation, and conflicting data have been obtained. Furthermore, whether CIP itself prolongs mechanical ventilation or whether this prolongation is the effect of concurrent risk factors for weaning failure is a matter of debate. Recent studies have contributed to our current knowledge about long-term prognosis and the impact of CIP on the length of hospital stay and inhospital mortality of critically ill patients with contradictory results. On the other hand, in this era of limited resources and expenditure containment, no study has attempted to assess the economic burden of these disorders. Further studies are warranted to assess whether various interventions that have been evaluated in heterogeneous groups of critically ill patients could help to reduce the rate of weaning failure and improve outcome of patients with CIP.