Agitation is a common occurrence in critically ill and palliative patients, and can be secondary to delirium, pain, and/or mechanical ventilation. Delirium, and associated agitation, is not only distressing to both patients and their families, it also increases a patient’s hospital stay, morbidity, and mortality. Agitation management includes pharmacological sedation with the use of antipsychotics, opioids, benzodiazepines, and propofol, but what are additional options when agitation persists? This course will review the role of ketamine, dexmedetomidine, phenobarbital, valproic acid, lithium, and novel approaches with antipsychotics to manage refractory agitation.