We have previously identified regions of human interferon-gamma (IFN-gamma) genomic DNA which can enhance gene expression in murine and human cells after linkage to a heterologous gene. One enhancer region of DNA lies in the 5' non-coding region of the gene, appears to be cell specific and is inducible by phorbol esters. The second enhancer region lies in the first intron, is not tissue specific, and is stimulated by PMA in T cells. These results indicate that control of IFN-gamma gene expression involves multiple DNA regions and that the role of these enhancer elements in gene expression may depend upon the signal transduction pathway utilized. This hypothesis is supported by the findings that interleukin-2 directly induces IFN mRNA in large granular lymphocytes but has no effect on IFN transcription in resting T cells, thus indicating that extra cellular signaling of gene expression is distinct in different lymphocyte subsets.