Hepatocyte nuclear factor 1alpha (HNF-1alpha) is a homeodomain-containing transcription factor and is important in postnatal growth and development in mice. In the HNF-1alpha-deficient liver, the expressions of a large set of growth hormone (GH)-responsive genes were significantly downregulated. By analyzing various HNF-1alpha mutant mice, we disclosed a mechanism by which hepatic HNF-1alpha regulates the expression of GH-responsive genes that are crucial for growth and development. We found that HNF-1alpha is required for the normal expression of glucocorticoid receptor (GR) specifically in livers. In the liver, GR, together with STAT5, is known to mediate the GH action by transactivating the GH-responsive genes that function in body growth and development. We further demonstrated that HNF-1alpha modulated GR gene expression by directly transactivating the GR gene promoter via a cryptic regulatory element located 3 bp upstream of the translation start site in exon 2 of the GR gene locus.