Clonidine is an antihypertensive agent with central and peripheral alpha-2 adrenergic effects. One of the postulated mechanisms of action is the release of endogenous opioids and/or the stimulation of opioid receptors in the central nervous system (CNS). Naloxone, a pure opioid antagonist, has demonstrated reversal effects from clonidine intoxication. During the past 10 y, 25 children with a mean age of 2 y were admitted for clonidine intoxication. Dosage varied widely, but as little as 0.1 mg caused significant signs and symptoms. The most common presenting findings were somnolence-lethargy (96%), miosis (56%), and respiratory depression (48%), a paradoxical hypertensive response (44%) was more common than expected. Supportive management was the mainstay of therapy. Ten patients received naloxone, 50% demonstrated clinical improvement in vital signs and CNS depression. There were no complications as a result of naloxone therapy. Children seem to be unusually sensitive to the depressant effects of clonidine. Naloxone may be an important adjunct to therapy. Expect clonidine intoxications to become more common as the market for antihypertensive drugs expands.