Perinatal exposure to phenobarbital produces a range of permanent reproductive, growth, locomoter, and learning dysfunctions in animals as well as humans. In addition, the affected individuals exhibit latently expressed (i.e., postpubertal) above normal activity levels of hepatic multicytochrome P450-dependent drug metabolizing enzymes. We report that in spite of apparent normal health for the better part of their lives, daily administration of therapeutic-like doses of phenobarbital to male and female rat pups during the first postpartum week reduced life expectancy by approximately 20%. Necropsy at the time of natural death revealed an associated two- to threefold increase in the incidence of tumors in barbiturate-exposed rats of both sexes and a three- to fourfold increase in urinary tract pathologies in male rats. At 2 yr of age, in agreement with an overexpression of hepatic CYP2C6 and CYP2C7, both in vitro and in vivo drug metabolism was more rapid in the phenobarbital-imprinted male and female animals. Moreover, when the senescent rats were rechallenged with a nominal dose of the barbiturate, males and females neonatally exposed to phenobarbital exhibited a dramatic overinduction of multicytochrome P450-dependent drug metabolizing enzymes as well as an overexpression of individual isoforms of cytochrome P450 implicated in enhanced susceptibility to tumorigenesis. Our findings support the growing realization that many adult diseases have their origins in early life by emphasizing that unlike adults, the new born is "plastic," and even therapeutic drugs may produce "silent" programming defects that subtly, but irrevocably, jeopardize life-long well-being.