Neuromuscular blockings agents (NMBAs) have a controversial role in the ventilatory and medical management of critical illness. The clinical concern surrounding NMBA-induced complications stems from evidence presented in the 2002 clinical practice guidelines, but new evidence from subsequent randomized trials and studies provides a more optimistic outlook about the application of NMBAs in the ICU. Furthermore, changes in the delivery of critical care, such as protocolized care pathways, minimizing or interrupting sedation, increased monitoring techniques, and overall improvements in reducing immobility, have created a modern, 21st century ICU environment whereby NMBAs may be administered safely. In this article we start with a review of the mechanism of action, side effects, and pharmacology of commonly used NMBAs. We then address the rationale for NMBA use for an expanding number of indications (endotracheal intubation, acute respiratory distress syndrome, status asthmaticus, increased intracranial and intra-abdominal pressure, and therapeutic hypothermia after cardiac arrest), with an emphasis on NMBA use in facilitating lung-protective ventilation for respiratory failure. We end with an appraisal over the importance of monitoring depth of paralysis and the concerns of complications, such as prolonged skeletal muscle weakness. In the context of adequate sedation and analgesia, monitored NMBA use (continuous or bolus administration) can be considered for the small number of clinical indications in critically ill patients for which evidence currently exists.