UDP-glucuronosyltransferases (UGTs) belong to the Phase II drug metabolizing enzymes. UGTs mediate the transfer of glucuronic acid, from UDP glucuronic acid to predominantly hydrophobic xeno- and endobiotic chemicals, thus facilitating their detoxification and excretion. Deficiency in the expression and/or activity of UGTs may lead to genetic and acquired diseases such as Crigler-Najjar syndrome and jaundice. UGT genes are classified into UGT1A and UGT2B subfamily, and each subfamily and each isoform shows tissue-specific distribution pattern. The underlying mechanisms for this tissue specificity are not fully understood. Emerging evidence have demonstrated that nuclear receptors (NR), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPAR), can regulate UGTs and this NR-mediated regulation may contribute to the tissue-specific expression pattern of UGTs. The regulations are believed to be both receptor- and UGT isoform-specific. In addition, UGTs are also subject to the regulation by aryl hydrocarbon receptor (AhR) and other tissue-specific transcription factors. Based on their capacity to catalyze the glucuronidation of xenobiotics and endobiotics, UGTs play an important role in hormonal homeostasis, energy metabolism, bilirubin clearance, and xenobiotic detoxification. Therefore, elucidating UGT regulation by nuclear receptors has broader significance in understanding UGTs function in various physiological and pathophysiological conditions.