A bulk of researches performed in the last decade highlighted the extraordinary biological properties of cholangiocytes involved in a number of important processes such as bile formation, proliferation, injury repair, fibrosis, angiogenesis and regulation of blood flow. Cholangiocytes proliferation is a key mechanism capable of conditioning the evolution of liver damage. Proliferating cholangiocytes, in fact, acquire the phenotype of neuroendocrine cells and secrete different substances which represent the tools of cross-talk with other hepatic cells. Recent advances on the molecular and cell biology of cholangiocytes are opening new potential therapeutic perspectives for the human chronic liver diseases.