The orphan nuclear receptor pregnane X receptor (PXR) is essential for the transcriptional regulation of hepatic xenobiotic enzymes including the cytochrome 3A isoenzymes. These enzymes are central to the catabolism and clearance of most endogenous sterol metabolites (endobiotics) and a vast diversity of foreign compounds (xenobiotics) including pharmaceuticals, pesticides, and toxins encountered through diet and environmental exposure. To explore a broader role of PXR in the mammalian xenobiotic response, we have conducted a unique microarray gene profiling analysis on liver samples derived from PXR knockout mice and mice expressing a constitutively active variant, VP-hPXR. This genetically guided expression analysis enables targeting and restriction of the PXR response to liver, and is devoid of side effects resulting from drugs and their metabolites. As with pharmacological studies, receptor-dependent genes include both phase I and phase II metabolic enzymes, as well as certain drug and anion transporters as principal PXR targets. Moreover, comparative analysis of data from both genetic and pharmacological arrays reveals a core network that represents a genetic description of the xenobiotic response.