The liver is the major organ for metabolism of drugs and other xenobiotics. Expression of many drug-metabolizing enzymes is not equally distributed throughout the liver: under normal conditions, many of them, including the most relevant members of the cytochrome P450 superfamily, are exclusively expressed in a hepatocyte subpopulation located near branches of the efferent central vein. Activation of different ligand-dependent transcription factors by exogenous compounds stimulates high expression of certain cytochrome P450 isoforms. This process also occurs preferentially in perivenous hepatocytes. The mechanisms, however, which determine the zone-specificity of basal and xenobiotic-induced expression of cytochrome P450 enzymes, have remained largely unknown for decades. Very recently, signaling through the Wnt/beta-catenin pathway has been implicated in the regulation of zonal gene expression in mouse liver. In this review, current knowledge of cytochrome P450 regulation by beta-catenin-dependent transcription is summarized and underlying molecular mechanisms are discussed.