Nursing management of pain, agitation, and delirium in mechanically ventilated patients is a challenge in critical care. Oversedation can lead to delayed extubation, prolonged ventilator days, unnecessary neurologic testing, and complications such as weakness and delirium. Undersedation can lead to self-extubation, invasive line removal, unnecessary patient distress, and injury to self or others. Acquiring an optimal level of sedation requires the bedside nurse to be more vigilant than ever with patient assessment and medication titration. This article provides a historical perspective of the management of pain, agitation, and delirium, and disseminates information contained in revised Society for Critical Care Medicine Clinical Practice Guidelines (January 2013) to promote their implementation in day-to-day nursing care.