Pregnane X receptor (PXR) and constitutively active receptor/constitutive androstane receptor (CAR) are xenobiotic-responsible transcription factors belonging to the same nuclear receptor gene subfamily and highly expressed in the liver. These receptors are activated by a variety of chemicals and play pivotal roles in many liver functions, including xenobiotic metabolism and disposition. Phenobarbital, an enzyme inducer and liver tumor promoter, activates both rodent and human CAR but causes liver tumors only in rodents. Although the precise mechanism for phenobarbital/CAR-mediated liver tumor formation remains to be established, intracellular pathways, including the Hippo pathway/Yes-associated protein-TEA-domain family members system and -catenin signaling, seem to be involved. In contrast to CAR, previous findings by our group suggest that PXR activation does not promote hepatocyte proliferation but it enhances the proliferation induced by various stimuli. Moreover, and surprisingly, PXR may have antitumor effects in both rodents and humans by targeting inflammatory cytokine signals, angiogenesis and epithelial-mesenchymal transition. In this review, we summarize the current knowledge on the associations of PXR and CAR with hepatocyte proliferation and liver tumorigenesis and their molecular mechanisms and species differences. SIGNIFICANCE STATEMENT: Pregnane X receptor and constitutively active receptor/constitutive androstane receptor have very similar functions in the gene regulation associated with xenobiotic disposition, as suggested by their identification as xenosensors for enzyme induction. In contrast, recent reports clearly suggest that these receptors play distinct roles in the control of hepatocyte proliferation and liver cancer development. Understanding these differences at the molecular level may help us evaluate the human safety of chemical compounds and develop novel drugs targeting liver cancers.