Cholangiocytes are the main cell type lining the epithelium of the biliary tree of the liver. This cell type has been implicated not only in diseases affecting the biliary tree but also in chronic liver diseases targeting other hepatic cells such as hepatocytes. However, the isolation and culture of cholangiocytes have been particularly arduous, thereby limiting the development of new therapies. The emergence of organoids has the potential to address in part this challenge. Indeed, cholangiocyte organoids can be established from both the intra- and extrahepatic regions of the biliary tree, providing an advantageous platform for disease modeling and mechanism investigations. Accordingly, recent studies on cholangiocyte organoids, together with the advent of single-cell -omics, have opened the field to exciting discoveries concerning the plastic nature of these cells and their capability to adapt to different environments and stimuli. This review will focus on describing how these plasticity properties could be exploited in regenerative medicine and cell-based therapy, opening new frontiers for treating disorders affecting the biliary tree and beyond.