Cholestasis results in the intrahepatic retention of cytotoxic bile acids (BA) and it can thus lead to liver injury. Hydrophilic BA ursodeoxycholic acid (UDCA) is currently used to treat cholestasis but its efficacy is limited. Nuclear receptors are key regulators of various processes including metabolism of xeno- and endobiotics such as BA and drugs. Recent studies have made significant progress in elucidating the mechanisms which regulate the BA metabolism by nuclear receptors. The nuclear receptor FXR plays the role of master regulator of BA homeostasis and is a promising drug target for cholestatic liver disease. In addition to FXR, the nuclear receptors CAR and PXR function as sensors of toxic byproducts and regulator of BA homeostasis. Ligands for both receptors including phenobarbital have been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge of the xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases.