In order to evaluate the roles of the RET proto-oncogene in normal human tissues and tumors derived from the neural crest cells, we examined the expression of RET in a variety of adult human tissues, pheochromocytomas, medullary thyroid carcinomas (MTCs), ganglioneuromas, and a neurinoma. Northern blot analysis demonstrated that RET is normally expressed in the adrenal medulla and cerebellum among adult human tissues. RET transcripts were detected in all of 11 sporadic and one familial pheochromocytomas. The levels of RET mRNA were higher in 8 of 12 pheochromocytomas than in the normal adrenal medulla, indicating that RET is overexpressed in the majority of sporadic pheochromocytomas. There was a considerable difference in the level of RET expression in each pheochromocytoma ranging from 0.2 to 10 times the transcripts found in the normal adrenal medulla. The sizes of the transcripts of 7.0, 6.0, 4.5, and 3.9 kb were the same as those found in the adrenal medulla, suggesting no rearrangements of the RET gene in pheochromocytomas. Southern blot analysis revealed neither amplification nor gross structural changes in the RET gene. RET was also expressed at high levels in four MTCs examined, whereas its transcripts were detected at low abundance in only one of three ganglioneuromas. RET was not expressed in a neurinoma. These results suggest that RET may play some roles in a limited range of adult human tissues, and that its high levels of expression may have relevance to development or growth of pheochromocytomas and MTCs.