The liver is essential for survival due to its critical role in the regulation 
of metabolic homeostasis. Metabolism of xenobiotics, such as environmental 
chemicals and drugs by the liver protects us from toxic effects of these 
xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and 
glucose provide key building blocks and nutrients to promote the growth or 
maintain the survival of the organism. As a well-established master regulator of 
liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays 
a critical role in regulating a large number of key genes essential for the 
metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and 
activity of HNF4α is regulated by diverse hormonal and signaling pathways such 
as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming 
growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role 
in orchestrating the transduction of extracellular hormonal signaling and 
intracellular stress/nutritional signaling onto transcriptional changes in the 
liver. There have been a few reviews on the regulation of drug metabolism, lipid 
metabolism, cell proliferation, and inflammation by HNF4α. However, the 
knowledge on how the expression and transcriptional activity of HNF4α is 
modulated remains scattered. Herein I provide comprehensive review on the 
regulation of expression and transcriptional activity of HNF4α, and how HNF4α 
crosstalks with diverse extracellular and intracellular signaling pathways to 
regulate genes essential in liver pathophysiology.