The expression of drug-metabolizing enzymes CYPs is controlled by pregnane X receptor (PXR), and, therefore, understanding how PXR modulates CYP expression is important to minimize adverse drug interactions, one type of preventable adverse drug reaction.We review the mechanisms of PXR-mediated repression of CYP expression.We discuss the clinical implications of CYP repression and the role of signal cross-talks, including protein-protein interactions and phosphorylation of PXR and coregulators, in inhibiting PXR and repressing CYP expression.Kinases such as cyclin-dependent kinase 2, protein kinase A, PKC and 70 kDa form of ribosomal protein S6 kinase repress CYP expression by phosphorylating and inhibiting PXR. Growth factor signaling represses CYP expression by phosphorylating and inhibiting forkhead in rhabdomyosarcoma, a co-activator of PXR. During inflammation, NF-kappaB represses both PXR and CYP expression through protein-protein interactions with the PXR pathway.