Several case reports of resistance to short-term administration of nondepolarizing neuromuscular blocking agents (NNMBAs) have been reported in research and surgical settings. Recently, several reports documented resistance to NNMBAs during therapy for prolonged paralysis in critically ill patients. Adverse outcomes associated with NNMBA resistance may include inadequate ventilatory management or suppression of patient movement, and an increased risk of dose-dependent cardiovascular adverse effects. Pharmacoeconomic issues must be considered in that the cost of NNMBA therapy in a resistant patient may be significant. Although the specific etiologies of resistance are not clear, several pharmacodynamic and pharmacokinetic alterations may occur as a consequence of disease state or concomitant drug therapy. Pharmacodynamic changes include altered acetylcholine receptor physiology or sensitivity, inhibition of serum cholinesterase activity, and interaction with plasma constituents. Alterations in distribution volume, protein binding, and clearance may also contribute to resistance in several disease states.