Radiotherapy administrated to patients with head and neck malignancies and prior to bone marrow transplantation often results in severe xerostomia. We evaluated the expression of early response proto-oncogenes (c-fos and jun B), tissue specific genes (proline rich protein [PRP] and kallikrein), and proteolysis linked utiquitin gene following exposure to 15 Gy irradiation alone or in combination with beta-adrenergic stimulation of the rat submandibular glands. Head and neck irradiation resulted not only in dysfunction and tissue loss of the salivary glands but also in a systemic effect expressed as profound body weight loss. Irradiation alone was found to induce expression of the jun B but not the c-fos proto-oncogenes. The combination of irradiation and beta-adrenergic stimulation by isoproterenol induced earlier expression of jun B and profound expression of the c-fos proto-oncogene in comparison to irradiation alone. In contrast, the kallikrein and ubiquitin genes were expressed constitutively and were not affected by irradiation alone or in combination with beta-adrenergic stimulation. In addition, irradiation had no effect on submandibular gland mRNA translation. We observed that the expression of the genes whose regulation is associated with DNA damage (i.e. jun B and c-fos) was enhanced by irradiation alone or in combination with isoproterenol administration. In contrast, the expression of genes associated with the routine functional integrity of the cell (i.e. kallikrein, ubiquitin, and PRP) was unaffected. These findings, in addition to delayed gland dysfunction, leads us to believe that the irradiation induced injury to the submandibular glands is to be attributed to reproductive stem cell death which may be partly obliterated in the clinical setting by better understanding.