Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which 
is frequently and highly expressed on carcinomas, tumor-initiating cells, 
selected tissue progenitors, and embryonic and adult stem cells. During liver 
development, EpCAM demonstrates a dynamic expression, since it can be detected 
in fetal liver, including cells of the parenchyma, whereas mature hepatocytes 
are devoid of EpCAM. Liver regeneration is associated with a population of 
EpCAM-positive cells within ductular reactions, which gradually lose the 
expression of EpCAM along with maturation into hepatocytes. EpCAM can be 
switched on and off through a wide panel of strategies to fine-tune 
EpCAM-dependent functional and differentiative traits. EpCAM-associated 
functions relate to cell-cell adhesion, proliferation, maintenance of a 
pluripotent state, regulation of differentiation, migration, and invasion. These 
functions can be conferred by the full-length protein and/or EpCAM-derived 
fragments, which are generated upon regulated intramembrane proteolysis. Control 
by EpCAM therefore not only depends on the presence of full-length EpCAM at 
cellular membranes but also on varying rates of the formation of EpCAM-derived 
fragments that have their own regulatory properties and on changes in the 
association of EpCAM with interaction partners. Thus spatiotemporal localization 
of EpCAM in immature liver progenitors, transit-amplifying cells, and mature 
liver cells will decisively impact the regulation of EpCAM functions and might 
be one of the triggers that contributes to the adaptive processes in 
stem/progenitor cell lineages. This review will summarize EpCAM-related 
molecular events and how they relate to hepatobiliary differentiation and 
regeneration.