alpha-Fetoprotein (AFP) is one of the major serum proteins in the early life of mammals. The function of this protein is not yet fully understood. AFP is an oncodevelopmental gene product which is expressed at high levels in the embryonic yolk sac and fetal liver. The synthesis of AFP decreases dramatically after birth. Only trace amounts of AFP are synthesized in the adult liver. However, expression of the AFP gene is reactivated in the adult during liver regeneration and hepatocarcinogenesis. AFP is an excellent model system for studying the temporal and tissue-specific regulation of oncodevelopmental gene expression. Experiments with transgenic mice and DNA transfection studies have revealed several transcriptional control regions and cis-acting elements in the AFP gene. A large number of trans-acting protein factors interacting with these cis-acting elements have also been identified. Recent studies demonstrated that expression of AFP is regulated by at least two major signal transduction pathways in response to extracellular stimuli. The interactions between steroid hormone receptors and transcriptional factors which respond to separate signal transduction pathways result in transcriptional regulation of AFP gene expression. Trans-acting protein factors or steroid receptors complexed with given response elements can display different activities in different cell types due to cross-talk among both local protein-protein interactions within the DNA-binding domain, and distal protein-protein interactions. However, the detailed mechanisms of AFP gene expression are still not completely understood.