We have examined the patterns of mRNA accumulation and transcription of the tandemly linked genes for tumor necrosis factor (TNF)-beta and TNF-alpha. In spite of their tandem arrangement and close linkage, the two TNF genes utilize separate promoters. Our results show that, while levels of mRNA correlate with patterns of TNF-alpha and TNF-beta secretion by lymphocytes and macrophages, the transcriptional levels of the corresponding genes do not. The TNF-alpha gene is transcribed much more heavily than the TNF-beta gene in T lymphocytes, even though the TNF-beta mRNA is more abundant. Resting T lymphocytes and macrophages, which do not accumulate any TNF mRNA, nevertheless transcribe the TNF-alpha gene actively. On the other hand, the TNF-beta gene is transcriptionally silent in macrophages. Our results are consistent with a model where tissue specificity is controlled transcriptionally, whereas post-transcriptional events differentially control mRNA abundance.