Bed rest is a commonly prescribed activity restriction among patients in the ICU. Although bed rest may promote rest, recovery and safety, inactivity related to bed rest also may lead to complications and adverse outcomes. The biological mechanisms that lead to immediate and long-term sequelae from bed rest have not been elucidated. It may be the inflammatory factors common to critical illness combined with bed rest lead to a positive feedback loop, contributing to inflammatory disequilibrium. This disequilibrium has a profound affect on muscles. Muscle decay has serious and long-term adverse outcomes on survivors of critical illness. Mobility therapy may improve inflammatory disequilibrium and preserve muscles, leading to improved functional outcome. Investigations in the laboratory, in healthy people and among patients with systemic inflammatory disease, suggest that activity does not exacerbate inflammation. Clinically, exercise is beneficial to patients with various chronic inflammatory diseases. Further study is needed to best understand the role, duration, and frequency of activity in promoting recovery for critically ill patients.