Hepatic nuclear factor-4 (HNF-4) is a transcription factor and a member of the large family of nuclear receptors. It was first cloned from liver but is expressed also in kidney, pancreas and intestine. Three genes encoding three isoforms have been identified, HNF- 4α and γ, in mammals, drosophila and xenopus and HNF-4β, exclusively in xenopus. HNF-4α is the best studied isoform, especially in liver. Such studies put HNF-4α at the crossroads between architecture and function of epithelia, as it induces expression of cell/cell junction proteins while it also controls glucido-lipidic metabolism and drug metabolizing enzyme genes. Furthermore, mutations in the HNF-4α gene lead to a metabolic disease in humans, Maturity Onset Diabetes of the Young-1 (MODY-1). The existence of a “true ligand” is not clearly established but a “structural” fatty acid is present in the ligand binding pocket of HNF-4α and γ. Consequently, activity of HNF-4 can be modulated by the interaction with co-regulators or by post-translational modifications. Then, HNF-4 is a potential direct or indirect target for pharmacologic drugs, with a special interest for the intestinal epithelium which is the primary site of metabolic control, due to its roles in nutrient absorption and in sensing energy. The patents related to the HNF-4α gene are also discussed in this article.