Primary hepatocytes as liver stem cells can proliferate under liver injury. Hepatocytes are the major parenchymal cells (PC) in the liver and play an important role in liver metabolism. Hepatocytes are considered as a gold standard tool for drug toxicity/screening or liver disease modeling. Though the maturation and functions of hepatocytes are lost under routine 2-dimensional (2D) culture conditions. Recent studies revealed that interactions of hepatocytes with non-parenchyma cells (NPC) under 3D culture conditions can be an alternative option to overcome these problems. Co-culture of hepatocytes with NPC facilitated in-vitro liver disease models such as fibrosis, steatosis and non-alcoholic fatty liver disease (NAFLD), cholestasis, and viral hepatitis. This review described the co-culture of liver PC with NPC under 2D and 3D culture systems.