The development of neuromuscular dysfunction (NMD) during critical illness is increasingly recognized as a cause of failure to wean from mechanical ventilation and is associated with significant morbidity and mortality. At times it is difficult to identify the presence of NMD and distinguish the etiology of the weakness in patients with critical illness, but subtle clinical findings and bedside electrophysiological testing are helpful in establishing the diagnosis. The purpose of this review is to describe the clinical spectrum of acquired neuromuscular weakness in the setting of critical illness, provide an approach to diagnosis, and to discuss its pathogenesis. Finally, we propose defective sodium channel regulation as a unifying mechanism underlying NMD in critically ill patients.