Carbon monoxide (CO) poisoning is the leading cause of poisoning deaths (accidental and intentional) in the United States. While confirmation of CO poisoning is easily obtained via assessment of carboxyhemoglobin (COHgb) levels, evaluation of the severity of intoxication is both difficult and inconsistent. Acute intoxication most commonly results in neurologic dysfunction and/or myocardial injury. Delayed neurologic sequelae are observed in approximately 10% of patients. New information from clinical observations and animal research has prompted a re-evaluation of the clinical assessment of the severity of CO intoxication and its resultant pathophysiology. Patients at the extremes of age (the very young and the elderly), those with pre-existing cardiovascular and/or pulmonary disease, as well as pregnancy are at increased risk. Once the diagnosis of CO poisoning has been established, treatment with 100% O2 is indicated. Based on the body of clinical, basic and scientific information currently available, patients who manifest signs of serious intoxication (i.e., unconsciousness or altered neurologic function, cardiac or hemodynamic instability) should be considered candidates for hyperbaric oxygen therapy (HBO) in addition to other appropriate supportive and intensive care. Any patient who has suffered an interval of unconsciousness, regardless of the patient's clinical exam on arrival, warrants HBO therapy. Treatment plans based on any specific COHgb level are not well founded.