The pregnane X receptor is an essential component of the body's detoxification system. PXR is activated by a broad spectrum of xenobiotics and endobiotics, including bile acids and their precursors. Bile acids in high concentrations are toxic; therefore their synthesis is tightly regulated by the farnesoid X receptor and their catabolism involves several enzymes regulated by PXR. Here we demonstrate that the expression of PXR is regulated by FXR. Feeding mice with cholic acid or the synthetic FXR agonist GW4064 resulted in a robust PXR induction. This effect was abolished in FXR knockout mice. Long time bile acid treatment resulted in an increase of PXR target genes in wildtype mice. A region containing four FXR binding-sites (IR1) was identified in the mouse Pxr gene. This region was able to trigger an 8-fold induction after GW4064 treatment in transactivation studies. Deletion or mutation of single IR1 sites caused a weakened response. Importance of each individual IR1 element was assessed by cloning a triple or a single copy and tested in transactivation studies. Two elements were able to trigger a strong, one a moderate and one no response to GW4064 treatment. Mobility shift assays demonstrated that the two stronger responding elements were able to bind FXR protein. This result was confirmed by chromatin-immunoprecipitation. These results strongly suggest that PXR is regulated by FXR. Bile acids activate FXR, which blocks synthesis of bile acids and also leads to the transcriptional activation of PXR, promoting breakdown of bile acids. The combination of the two mechanisms leads to an efficient protection of the liver against bile acid induced toxicity.