Impaired physical function and reduced physical activity are common findings in intensive care unit (ICU) survivors. More importantly, reduced muscle strength during critical illness is an independent predictor of survival. Skeletal muscle wasting as a direct consequence of critical illness has been suggested as the cause. However, data on the physiological processes regulating muscle mass, and function, in these critically ill patients are limited as this is not only a technically challenging research area, but also the heterogeneity of the patient group adds complexity to the interpretation of results. Despite this, clinical and research interest in this area is growing. This article highlights the issues involved in measurement of muscle function and mass in critically ill patients and the physiological complexities involved in studying these patients. Although the data are limited, this article reviews the animal and healthy human data providing a rational approach to the potential pathophysiological mechanisms involved in muscle mass regulation in critically ill patients, including the established muscle wasting 'risk factors' such as ageing, immobility and systemic inflammation, all of which are common findings in the general critical care population.