The effects of streptozotocin-induced diabetes on the function and pattern of innervation of the rat parotid gland were investigated. An in vitro preparation was used to measure amylase release and immunohistochemistry was used to examine the innervation of the gland. Basal amylase release and the response to field stimulation were reduced in diabetic animals. In the presence of atropine or a propranolol/phentolamine mixture both control and diabetic responses were attenuated. When all 3 antagonists were present the response to field stimulation (non-adrenergic, non-cholinergic [NANC] response) was about 30% of maximal in untreated rats but virtually abolished in diabetic animals. Substance P (SP), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) all stimulated amylase release in untreated rats. However, in diabetic rats the responses to all 3 peptides were reduced. No differences in staining were observed between control and diabetic rats with antisera to tyrosine hydroxylase, substance P. VIP or calcitonin gene-related peptide. In contrast there was a marked reduction in NPY-like immunoreactivity in the acinar tissue of diabetic rats. These data suggest that the diabetic rats had a failure of NANC transmission which appears to be due to a reduced NPY innervation and a lack of responsiveness to peptidergic (SP, VIP and NPY) agonists.