Non-alcoholic fatty liver disease (NAFLD) is one of the most prominent causes of liver-related morbidity in the Western world. NAFLD is a chronic disease characterised by accumulation of triglycerides in hepatocytes. Upon damage, hepatocytes drive regeneration to sustain homeostasis of the liver. However, 30-40 years of ongoing replication induced by chronic lipid damage and oxidative stress increase senescence of the hepatocytes. At this stage, activation of a reserve compartment is seen, known as the hepatic progenitor cells (HPCs). HPCs are bipotent cells which can differentiate into hepatocytes or cholangiocytes depending on the underlying aetiology in order to facilitate liver regeneration. Activation of HPCs is observed as ductular reaction (DR), comprising an expansion of transit amplifying cells of the terminal branches of the biliary tree. DR is usually observed in advanced NAFLD but is also associated with histological severity and distinct molecular profiles. In this context, information about HPCs and their activation in the form of DR may add a both diagnostic and prognostic values when assessing NAFLD patients. In this review, we analyse HPCs characteristics and development, and the clinical impact of their activation in subjects with NAFLD.