The interindividual variability of expression of genes encoding drug metabolizing enzymes and transporters contributes significantly to human drug disposition. Their expression is largely controlled by transcription factors at the level of transcription initiation. Improving our knowledge of variable drug disposition thus requires a well-founded and detailed understanding of the respective molecular mechanisms of transcriptional regulation. Members of the nuclear receptor (NR) family of transcription factors play a decisive role in transcriptional regulation of these genes, as they contribute both to constitutive and inducible expression. The xenosensing nuclear receptors PXR and CAR are here of special interest, as induction by xenobiotics, including many drugs, often results in drug-drug interactions with potential severe clinical consequences. Our research aims to elucidate the molecular mechanisms of ADME gene regulation by NRs, especially PXR and CAR, by identifying and characterizing the relevant cis-acting sequences in promoters and enhancers of regulated genes as well as identifying the trans-acting proteins (e.g. co-activators and co-repressors), which interact with the NRs in the regulation of their target genes. Furthermore, we are interested in the interplay of NRs and epigenetic modifications in the chromatin of the theses genes. In addition to molecular and biochemical approaches, we use comparative genomics to analyze the evolutionary conservation of gene-regulatory mechanisms. We currently focus on drug transporter genes and selected ABCB1, one of the most important human drug transporters, as the paradigm gene for our analyses.