Delirium is a serious and common problem in severely medically ill patients of all ages. It has been less addressed in children and adolescents. Treatment of delirium is predicated on addressing its underlying cause. The management of its symptoms depends on the off-label use of antipsychotics, while avoiding agents that precipitate or worsen delirium. Olanzapine, quetiapine, and risperidone are presently considered first-line drugs, usually replacing haloperidol. Other agents have shown promise, including melatonin to address the sleep disturbance characteristic of delirium, and dexmedetomidine, an α2-agonist, that may facilitate lower doses of benzodiazepines and opioids that may worsen delirium.