Recent findings indicate that the function of metabolically relevant genes is finely regulated at the level of gene transcription. Disturbances of these regulatory pathways often lead to metabolic unbalance and to the onset of socially relevant diseases, i.e. diabetes, metabolic syndrome, atherosclerosis and cardiovascular diseases. The ability of lipid metabolites, such as fatty acids and oxysterols, to signal to cells and tissues and to affect gene transcription by activating specific nuclear receptors has been known since several years. Bile acids have been known in the past as cholesterol end products, purely acting as detergents. Only recently new biological properties of bile acids as signaling molecules have been disclosed and appreciated. In this review, we will describe how bile acids can regulate their own synthesis and other metabolic pathways (i.e. glucose metabolism) by modulating gene transcription through multiple mechanisms. These findings also open new perspectives towards the exploitation of bile acid metabolism as a pharmacological target.