Critical illness is a pathophysiological stress response that typically requires mechanical ventilation and hemodynamic support in an intensive care unit (ICU). Allostatic mechanisms tailor the critically ill state and eventually downregulate the stress response. Failure to downregulate the stress response can lead to increased morbidity and mortality. In general, ICU care focuses on component organ system physiology and prioritizes cardiopulmonary function. However, vast knowledge gaps exist in understanding why some patients simply fail to recover from a prolonged critical illness condition. In this review, we present an integrative physiology approach to the metabolic care in critical illness with an emphasis on skeletal allostasis. In particular, we discuss the different allostatic responses and their effects on bone in acute, prolonged, and chronic critical illness, currently available clinical interventions targeting skeletal remodeling, and emergent biological therapies with skeletal effects. It is hoped that by shifting the paradigm to a systems approach, some of the significant knowledge gaps can be closed and critical illness outcomes can be improved.