Reports have appeared recently which propose the administration of phenobarbital during the perinatal period in order to reduce neonatal hyperbilirubinemia. One investigator also has suggested that phenobarbital was responsible for a decline in the death rate among small newborn infants. Since phenobarbital is known to alter the cellular metabolism of many compounds in addition to bilirubin, a brief review of present knowledge and comments on the possibility of unintentional effects of this drug in the perinatal period are warranted. It must be understood that much of the information on the effects of phenobarbital in animals may eventually have little or no clinical relevance; but, knowledge of the experimental evidence concerning the multisystem action of phenobarbital should help to identify areas of study and surveillance in the human subject.