Cholangiopathies are characterized by a predominately bile duct-directed inflammatory response that leads to bile duct injury and, if the injury is persistent, bile duct loss and the chance of developing bile duct cancer (cholangiocarcinoma). Although the cholangiopathies have broad range of etiologies and pathogenesis (eg, inherited disorders, autoimmune disorders, infections, drug-induced, ischemia, and unknown etiology), all share the common pathogenetic target-the biliary epithelial cell (cholangiocyte). For the most part, the pathogenesis of these diseases is poorly understood, which correspondingly has restricted clinicians to nonspecific and usually ineffective therapies for these disorders. Nevertheless, significant advances toward the understanding of the mechanisms involved in cholangiocyte-directed inflammation, biliary fibrosis, cholangiocyte death, and cholangiocarcinoma have unfolded over the past 15 years that may provide us new hopes and schemes for treatment of these disorders.