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The molecular basis for the pituitary‐specific expression of the human growth hormone (hGH) gene was investigated, by gene transfer and protein footprinting experiments. Plasmid constructs in which CAT or Neo transcription units are fused to a 0.5 kb fragment of the hGH 5′ sequences were efficiently expressed in GC and GH3 cells, derived from a pituitary tumor, but not in cell lines of other origins, indicating the presence of a tissue‐specific promoter. DNaseI footprinting experiments have identified at least three factors that specifically bind to the hGH 5′ region. While two of these factors were also detected in extracts of non‐expressing cells, the third factor, GHF‐1, was detected only in extracts of GH expressing pituitary tumor cells. Mutagenesis experiments suggest that binding of GHF‐1 and some of the other more ubiquitous factors is required for optimal hGH promoter activity in vivo. Tissue specificity of the hGH promoter therefore seems to be determined by the binding of at least one tissue‐specific trans‐acting factor, acting in concert with several other more ubiquitous, yet specific, DNA binding proteins.