Retinoic acid receptors (RARs), retinoid X receptors (RXRs) and thyroid hormone receptors (TRs) are nuclear receptors that are crucial transcriptional regulators of many cellular processes such as differentiation, development, apoptosis, carbohydrate and lipid metabolism, homeostasis etc. In addition, RXRs are common heterodimerization partners for several receptors including vitamin D receptor, pregnane X receptor (PXR), constitutive androstane receptor (CAR) etc. In the course of 90s, PXR and CAR were discovered as key xenosensors regulating drug-metabolizing enzymes. Since there exist various cross-talks between cell signaling pathways, this was not surprising that RXRs, RARs and TRs were identified as regulators of human drug-metabolizing cytochromes P450 and cytochromes P450 involved in metabolism of endogenous compounds. Hence, a link between regulation of xenobiotic metabolizing enzymes and regulatory pathways of intermediary metabolism was established. Additionally, several drug-metabolizing enzymes are involved in metabolism of retinoids, rexinoids and thyroid hormones. In the current paper, we summarize the knowledge on the role of RARs, RXRs and TRs in the regulation of drug metabolizing cytochromes P450, and vice versa on the role of P450s in homeostasis of retinoids, rexinoids and thyroid hormone.