The farnesoid X receptor (FXR) is a member of ligand-activated nuclear receptor superfamily. FXR is a bile sensor and is part of a complex network of nuclear receptors that includes also the constitutive androstane receptor and the pregnane X receptor. These receptors act coordinately to regulate essential steps of bile acids and xenobiotics uptake, metabolism and excretion in hepatocytes, cholangiocytes and kidney cells. Preclinical models indicate that FXR agonists are effective in reducing liver injury in nonobstructive models of cholestasis. FXR ligands are currently under investigation for treating patients with early stage primary biliary cirrhosis. Although these ligands hold promise, evidence is growing that FXR activation could impair the expression/activity of basolateral transporters such as multidrug resistance protein 4 essential for basolateral secretion of bile constituents in the systemic circulation. Because FXR, pregnane X receptor and constitutive androstane receptor ligands interact with different target genes, it appear that a combination with pregnane X receptor, constitutive androstane receptor ligand/activator or both or ursodeoxycholic acid could prevent possible side-effects of FXR activation in severe cholestasis.