The farnesoid X receptor (FXRalpha) is a metabolic nuclear receptor and bile acid sensor expressed in the liver and intestine. Physiological studies have shown that FXRalpha exerts regulatory roles in bile acids, lipid and glucose homeostasis. FXR ligands of steroidal and non-steroidal structure have been described. Both ligand groups have shown limitations in preclinical studies regarding their absorption, metabolism, target interactions and intrinsic toxicity. Inhibition of bile acid synthesis and basolateral transporters in the liver as well as reduction of high density lipoprotein (HDL) in the plasma are the major unwanted effect seen with these ligands. Several FXRalpha modulators are currently being generated with the aim of targeting FXRalpha isoforms by exploiting the relative unselectivity of the ligand binding domain of the receptor. Structure-activity relationship studies have shown that FXRalpha could be activated by structurally different ligands and that receptor occupancy by these ligands generate different patterns of gene activation as a results of specific conformational changes of the receptor or differential dislodgement of co-repressor or recruitment of co-activators. Generation of modulators that selectively target specific FXRalpha responsive elements are an interesting strategy to overcome the limitations of currently available FXR ligands.