Thyroxine and glucocorticoids both play important roles in regulating the development of mammalian tissues. The mechanisms by which they modulate the developmental process is not fully understood. Furthermore, the interaction between the effects of two hormones on the pancreas has not been studied in detail. To investigate these issues, we studied the effect of thyroxine and/or corticosterone on the development of the exocrine pancreas in normal and adrenalectomized rats. Daily injection of thyroxine (0.1 micrograms/g body wt) to pups starting at day 5 of age resulted in precocious increases of exocrine enzymes in the pancreata of these pups. Hypothyroid pups, induced by propylthiouracil, exhibited suppression of development of their pancreatic exocrine enzymes. Replacement of thyroxine or corticosterone alleviated the suppression of exocrine enzyme development in these pups. Rat pups, who underwent adrenalectomy at 5 days of age, had undetectable plasma corticosterone and exhibited similar suppression of pancreatic enzyme development. Injection of thyroxine or corticosterone alone to adrenalectomized pups led to normal development of exocrine pancreatic enzymes. When both thyroxine and corticosterone were given together to adrenalectomized pups, their pancreatic enzyme levels were found to increase to values above those of pups treated with thyroxine or corticosterone alone. We conclude that thyroxine has both direct and indirect modulatory roles in the development of the rat exocrine pancreas. Normal development of the exocrine pancreas depends on both intact adrenal and thyroid function in the rat.