Advances in medicine and technology have improved the survival of critically ill patients, but have also created a new category: the chronically critically ill patient. These patients have prolonged dependence on mechanical ventilation (MV) and other complex conditions that present significant challenges to their management and rehabilitation. Chronic critical illness is associated with muscle weakness, neuropathy, delirium, and other complications. Prolonged mechanical ventilation (PMV) is common in this group and is associated with comorbidities and risk factors. Despite advances in rehabilitation, clinical outcomes remain inconsistent and associated costs are substantial. Specialized PMV rehabilitation centers offer a comprehensive approach that may improve outcomes, but there is still a lack of consensus on criteria and methods for weaning from mechanical ventilation. This chapter discusses the challenges and options for care of chronically critically ill patients, emphasizing the importance of a multidisciplinary approach.