Recent discoveries highlighted intriguing molecular pathways that regulate synthesis, uptake, metabolism and excretion of bile acids and xenobiotics. The knowledge of factors that control these homeostatic processes is of clinical relevance to better understand the drug-drug interacting scenario as well as to control cholesterol detoxification, cholestasis and other conditions. Here we present evidences for the existence of a gut-liver safety network whereby activation of the nuclear receptor FXR, PXR, CAR trio provides protection against accumulation of exogenous and metabolic noxae.