Recent studies have established that bile salts are signaling molecules, besides their classic function in dietary lipid absorption and cholesterol metabolism. Bile salts signal by activating mitogen-activated protein kinase (MAPK) pathways and nuclear receptors like farnesoid X receptor-alpha (FXRalpha). FXRalpha activation increases the expression of direct FXRalpha target genes involved in bile salt transport and detoxification, and decreases expression of indirect FXRalpha target genes involved in bile salt biosynthesis and uptake. These actions prevent toxic accumulation of bile salts in the enterohepatic organs. A network of interactions with other nuclear receptors and MAPK pathways may protect the liver against pathological elevation of bile salts and cholestasis. Therefore treatment of cholestasis might benefit from the development of FXRalpha agonists.