Nondepolarizing neuromuscular blocking agents (NNMBAs) are commonly used in the intensive care unit (ICU), mainly to facilitate mechanical ventilation in critically ill patients who are not responding to sedatives and analgesics alone. Tachyphylaxis, also referred to as resistance, may develop during long-term infusion of NNMBAs. Several case reports of tachyphylaxis to NNMBAs have been reported. Although the definite mechanisms of tachyphylaxis to NNMBAs are not clear, several pharmacodynamic and pharmacokinetic changes have been described with the development of resistance. Tachyphylaxis to NNMBAs is associated with adverse outcomes including inadequate ventilation, increased risk of dose-dependent side effects, and increased drug costs. Patients who develop tachyphylaxis to one NNMBA should be treated with another NNMBA if neuromuscular blockade (NMB) is still indicated. We report three cases of tachyphylaxis to cisatracurium in a surgical intensive care unit (SICU): one in patient with acute respiratory distress syndrome (ARDS) and the other two with traumatic brain injury (TBI).