ICU-acquired weakness (ICUAW) is a frequent disabling disorder that can occur in ICU subjects. Given that the disorder can involve the muscular and peripheral nervous systems, many definitions have been suggested including critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and critical illness polyneuropathy and myopathy (CIPNM), but until now no definition has obtained unanimous consensus. With regard to this issue, ICUAW is proposed to overcome nomenclature classification problems [
1] even if CIPNM is also broadly accepted. Although clinical assessment of muscle weakness using the Medical Research Council (MRC) score can quantify strength impairment, differentiation of the ICUAW types is not possible on the basis of the clinical picture, and electromyography (EMG) remains the hallmark in diagnosing and differentiating ICUAW types, particularly in volitional subjects. Since the first description by Bolton et al. [
2], ICU specialists have carried out a number of investigations that have provided important progress in understanding several aspects of ICUAW, including its pathogenic mechanisms as well as electrophysiological [
3] and histological pictures [
4]. Recently, a reduction in the sodium channel subtype Nav1.6 was found on the sural nerve of ICU patients by Li et al. [
5], who also observed production of antibodies against all three major sodium channels (Nav1.6, Nav1.8, Nav1.9) which have a major role in the initiation and conduction of action potentials. Furthermore, experimental animal model studies in rats have demonstrated a hyperpolarized shift in the voltage dependence of sodium channels [
6] and impaired Ca
2+ release, which induce muscle membrane inexcitability and muscle weakness [
7]. These findings support pioneering studies hypothesizing that the pathological mechanism responsible for CIM could be due to muscle membrane inexcitability [
8]. On the other hand, although great progress has been made by ICU specialists, several areas of uncertainty persist that should be addressed in future research [
9]. Among these, pharmacological therapy to prevent and better manage this disorder has remained unsatisfactory. Indeed, despite the number of therapeutic interventions investigated, including antioxidant and nutritional agents, corticosteroids, and intravenous immunoglobulins, only intensive insulin therapy has been demonstrated to produce some benefit [
10]. Likewise, nonpharmacological treatments have been ineffective, apart from early physical therapy which has been found to reduce the duration of mechanical ventilation [
10]. Other important issues that should be addressed concern the functional outcomes and long-term recovery of ICUAW subjects.