Patients with critical illness are at risk of profound weakness and skeletal muscle loss, and recovery is marked by prolonged physical functional impairment in many survivors. Muscle and nerve abnormalities found in critically ill patients include loss of muscle mass, muscle membrane inexcitability, polyneuropathy, mitochondrial dysfunction with bioenergetic failure, as well as changes in skeletal muscle structure. The most common histological abnormalities are atrophy of both type I and II fibres and thick filament loss; muscle necrosis is less common. While recent studies have illuminated the pathogenesis of critical illness myopathy, additional high-quality translational research is needed to identify targets for therapeutic intervention.