It is essential that spontaneous tumours in rodents are accurately diagnosed and recorded in carcinogenicity studies, so that any response to the administered compound can be accurately assessed. The objective of the present research investigation was to utilize molecular techniques, in association with conventional histopathology, to systematically evaluate lung tumours in B6C3F1 mice and thyroid gland tumours in Han Wistar rats. The overall aim was to improve diagnostic accuracy and, if possible, determine the histogenesis of these lesions. In the first part of this investigation, primary lung tumours in B6C3F1 mice revealed a high degree of structural and functional differentiation, with surfactant protein (SP) mRNAs being detected in the majority of alveolar/bronchiolar neoplasms. The presence of SP mRNAs was also observed in normal and hyperplastic alveolar type II cells but not in the bronchiolar epithelium. These findings provide strong support for the proposal that such tumours should be referred to as alveolar (not bronchiolar) adenomas and carcinomas. Pulmonary metastases of hepatocellular carcinoma (HCC) were generally much less differentiated and exhibited a wider range of morphologies. Many of these deposits were anaplastic and approximately 36% showed undetectable levels of albumin mRNA. Thyroid tumours in the Han Wistar rat were evaluated in the second part of this investigation, with the majority of tumours showing the differentiated features of either C-cell or follicular neoplasms. In general, C-cell lesions comprised well differentiated cells that continued to express calcitonin even after embolic spread and metastasis. The increased expression of somatostatin in the smaller C-cell lesions indicated a possible growth inhibitory effect of this peptide. Follicular lesions presented a more diverse range of morphological patterns but, with the exception of solid types, the production of thyroglobulin was a consistent feature. The absence of any tumour showing a combination of follicular and C-cell differentiation, would appear to lend support to the concept that follicular cells and C-cells originate from separate germ layers (endoderm and neuroectoderm) in the rat.