Cholangiocytes constitute the biliary epithelium, an important barrier to infection entering the liver via the gastrointestinal tract. These cells have developed mechanisms to respond to infection by recruiting and interacting with effector leukocytes to clear bacterial or viral pathogens. Cholangiocytes are also targets of immune mediated damage in several liver diseases and under these circumstances protective mechanisms, for example the secretion of chemokines and expression of adhesion molecules, become harmful and promote the inappropriate recruitment and retention of effector cells within portal tracts. In chronic inflammatory biliary diseases such as primary biliary cirrhosis and primary sclerosing cholangitis, infiltrating leukocytes destroy bile ducts by killing cholangiocytes via complex molecular mechanisms involving Fas-dependent apoptosis and autocrine and paracrine interactions with other members of the TNF superfamily including CD40. A better understanding of these processes may lead to novel therapeutic approaches aimed at switching off the chronic inflammatory response and protecting bile ducts from apoptosis.