It was demonstrated that the altered endocrine environment caused by caffeine consumption could be equated with a stress-like pattern of response. A single acute treatment with caffeine (30 or 60 mg/kg) to male rats approximately 85 days old caused plasma concentrations of corticosterone, progesterone, testosterone and Na+ to rise significantly above control values. These changes were evident 3 min after caffeine administration and were maintained for 1-4 h before returning to normal. In animals exposed to daily chronic caffeine treatment for 10 days or more the levels of progesterone fell and Na+ rose significantly compared with control values at 24 h after administration. Following a single treatment of 30 mg/kg, caffeine was detected in blood plasma after 3 min, and reached peak levels by 1 h. After 24 h, less than 2% of the peak levels of caffeine remained. Metabolites of caffeine were detectable within 6 min and reached their peak levels 4 and 12 h later for theophylline and theobromine respectively. It is suggested that high steroid levels may in the long-term cause an altered hepatic clearance pattern affecting both steroid metabolism and caffeine elimination. A preliminary study of the morphology of livers from males chronically exposed to caffeine revealed that the hepatic cells lost cytoplasmic matrix, and that the sinusoids did not show up as clear spaces, compared with those in the controls.