Despite all we have learned, the reason why certain tumours and particularly non-pituitary tumours synthesize ACTH remains an enigma. There is no clear theory which links the neoplastic process with the expression of peptide hormones but it is interesting to speculate that the amplification of certain oncogenes may be linked to de-repression of hormone genes. Once the gene has been switched on, there should be some mechanism for preventing continuous expression and in the pituitary the POMC gene is normally inhibited by glucocorticoids. Therefore it is crucial to investigate the role of glucocorticoids in non-pituitary tumours and this requires an understanding of the molecular mechanisms involved in glucocorticoid inhibition of the normal POMC gene in the pituitary. The evidence presented in this chapter describing the glucocorticoid receptor binding site in the promoter region of the POMC gene in rat pituitary gives an exciting insight into the regulatory mechanisms and their potential for aberrant control. Taken with the presence of pituitary-specific regions regulating the POMC gene promoter there appear to be multiple approaches to dissecting out the differences in non-pituitary tumours. Thus in a relatively short period of time there has been a marked increase in our understanding of the molecular mechanisms underlying POMC gene expression. At the level of the peptides, progress has been slower. We are now aware that secretion of ACTH implies that a number of other peptides will be found in the circulation, even though there is limited evidence for a specific role for any of the co-secreted peptides. However, it is hard to understand the conflicting reports that N-POC is synthesized by non-small cell and small cell carcinoma of the lung when ACTH, which we assume to be co-secreted, is thought to be synthesized only by small cell carcinoma. The most likely explanation for this is the difficult nature of the radio-immunoassays for these hormones and the problems associated with studying large groups of clearly defined patients. Development of very simple methods for measuring the ACTH precursors has demonstrated that they are released into the circulation in normal subjects and that the levels are markedly elevated in non-pituitary tumours, suggesting that they are the major circulating forms in the ectopic ACTH syndrome. This implies that these tumours cannot process the precursor molecules suggesting that the processing enzymes are lacking.(ABSTRACT TRUNCATED AT 400 WORDS)