The immune system maintains the homeostasis of the biliary epithelium, where bile and cholangiocytes play an important role in modulating immune responses. Furthermore, cholangiocytes represent the target of the immune system in several hepatobiliary diseases (e.g., primary biliary cirrhosis). This article is organized into two parts. The first section reviews the role of cholangiocytes in the immune defense and the mechanisms by which cholangiocytes regulate immune responses. The expression of adhesion molecules on the cholangiocyte surface allows the interaction with immune cells, thus localizing and modulating the intensity of the immune reactions. Moreover, cholangiocytes secrete immunoglobulins, cytokines, and other mediators, which affect the functions of the surrounding liver cells, as well the cholangiocytes themselves. Cholangiocytes express major histocompatibility complex molecules, and thereby could act as antigen-presenting cells. In the second section, we describe how cytokines and inflammatory mediators modulate cholangiocyte function such as proliferation, apoptosis, secretion, and malignant transformation.