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 electrophysiologic testing are helpful in establishing the diagnosis. This article describes the clinical spectrum of acquired neuromuscular weakness in the setting of critical illness, provides an approach to diagnosis, and discusses its pathogenesis. Finally, a defective sodium channel regulation as a unifying mechanism underlying NMD in critically ill patients is proposed.