When robust clinical trials are lacking, clinicians are often forced to extrapolate safe and effective evidence-based interventions from one patient care setting to another. This article is about such an extrapolation from the intensive care unit (ICU) to the long-term acute care hospital (LTACH) setting. Chronic critical illness is an emerging, disabling, costly, and yet relatively silent epidemic that is central to both of these settings. The number of chronically critically ill patients requiring prolonged mechanical ventilation is expected to reach unprecedented levels over the next decade. Despite the prevalence, numerous distressing symptoms, and exceptionally poor outcomes associated with chronic critical illness, to date there is very limited scientific evidence available to guide the care and management of this exceptionally vulnerable population, particularly in LTACHs. Recent studies conducted in the traditional ICU setting suggest interprofessional, multicomponent strategies aimed at effectively assessing, preventing, and managing pain, agitation, delirium, and weakness, such as the ABCDEF bundle, may play an important role in the recovery of the chronically critically ill. This article reviews what is known about the chronically critically ill, provide readers with some important historical perspectives on the ABCDEF bundle, and address some controversies and practical implications of adopting the ABCDEF bundle into the everyday care of patients requiring prolonged mechanical ventilation in the LTACH setting. We believe developing new and better ways of addressing both the science and organizational aspects of managing the common and distressing symptoms associated with chronic critical illness and prolonged mechanical ventilation will ultimately improve the quality of life for the many patients and families admitted to LTACHs annually.