Human UDP-glucuronosyltransferase (UGT) 1A1 is the enzyme that detoxifies neurotoxic bilirubin by conjugating it with glucuronic acid. UGT1A1 also plays a critical role in the detoxification and excretion of endogenous and exogenous lipophilic compounds mainly in the liver and gastrointestinal tract. Impaired or reduced UGT1A1 activity causes unconjugated hyperbilirubinemia (Gilbert's syndrome and Crigler-Najjar syndrome) and side effects of drug treatment such as SN-38 (active metabolite of the anticancer drug irinotecan)-induced toxicity. Understanding the regulatory mechanism of human UGT1A1 expression is critical in treating patients with unconjugated hyperbilirubinemia and for effective drug treatment. We identified the distal enhancer module of the UGT1A1 gene and a single nucleotide polymorphism in it that significantly reduces the transcriptional activity associated with the manifestation of Gilbert's syndrome. This review describes the transcriptional regulation of the human UGT1A1 gene by transcription factors and their co-factors, the genetic polymorphism associated with reduced transcriptional activity, and the induction of UGT1A1 expression by non-genetic factors including environmental factors and its pharmacological and toxicological meaning.