Since the original description of the gene encoding apolipoprotein AI (apoAI) considerable progress has been made in identifying the regulatory regions and corresponding transcription factors that regulate its transcription in liver and intestinal cells. Nuclear receptors (in particular HNF-4) have emerged as the dominant (although by no means the exclusive) transcriptional activators that drive high levels of apoAI gene expression. In this review, some of the mechanisms (including interactions with recently described coactivators, as well as synergism with additional transcription factors bound to proximal and distal enhancers) that may underlie this process are discussed. Furthermore, apoAI gene expression has long been known to be subject to a variety of developmental, hormonal, dietary and pharmacological stimuli. The review thus also describes selected examples of these phenomena with the aim of highlighting how the operative transcriptional mechanisms are likely to be continually modified while maintaining the appropriate output.