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 wellestablished 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. 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, but 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 wellestablished 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 s tress / 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. Heartre I provides 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.