Hepatocyte nuclear factor 4alpha (HNF4alpha, NR2A1) is required for development of the liver and for controlling the expression of many genes specifically expressed in the liver and associated with a number of critical metabolic pathways. Among the genes regulated by HNF4alpha are the xenobiotic-metabolizing cytochromes P450, UDP-glucuronosyltransferases and sulfotransferases thus making this transcription factor critical in the control of drug metabolism. HNF4alpha, a member of the nuclear receptor superfamily, binds as a homodimer to direct repeat elements upstream of target genes. However, in contrast to many other nuclear receptors, there is no convincing evidence that HNF4alpha is activated by exogenous ligands, at least in the classic mechanism used by other steroid and metabolic nuclear receptors. X-ray crystallographic studies revealed that HNF4alpha has a fatty acid embedded in its putative ligand binding site that may not be easily released or displaced by exogenous ligands. HNF4alpha, as a general rule, controls constitutive expression of many hepatic genes but under certain circumstances can be subjected to regulation by differential co-activator recruitment, by phosphorylation and by interaction with other nuclear receptors. The ability of HNF4alpha to be regulated offers hope that it could be a drug target.