Stratum corneum barrier function in the female Fischer 344 rat was assessed in animals ranging from 11 to 144 weeks of age, which were either fed ad libitum or a caloric-restricted diet at 60% ad libitum. Caloric restriction has been shown to increase the life span of rodents and delay age-associated degenerative diseases. The penetration of water, lidocaine, and hydrocortisone were measured in vitro using the finite-dose technique in Franz diffusion chambers. Water permeability did not significantly change with either age or diet condition (with the single exception of the ad libitum 144-week animals). However, between 11 and 44 weeks, both lidocaine and hydrocortisone permeability increased with age in both diet groups. By 44 weeks the caloric restriction animals had significantly greater permeability to lidocaine and hydrocortisone then their ad libitum age cohorts. Between 44 and 144 weeks, skin permeability in the ad libitum animals continued to increase with age, whereas permeability in the caloric restriction animals declined. By 144 weeks the caloric restriction skin was less permeable than the age-matched ad libitum animals but still more permeable than the 11-week animals. The data show that the barrier properties of stratum corneum change with age in the female rat and that this change can be modulated by caloric restriction.