The liver is one of the vital organs in human beings. It is responsible for several functions such as energy homeostasis, detoxification, regulating blood sugar levels, protein synthesis, bile acid secretion, cholesterol production and glycogen storage. Hepatocellular Carcinoma (HCC) alternately referred to as malignant hepatoma accounts to ~75% of all liver cancers and its resistance to therapeutics at progressed stages makes it lethal. Some of the main causes of HCC include HBV, HCV, aflatoxin, chronic alcoholism, excess nutrition, liver cirrhosis, iron over load, Wilson's disease, and type 2 diabetes. It is essential to detect the underlying causes of HCC at the cellular and molecular levels to develop drugs and find a potential cure for the disease. Several ongoing studies on HCC cell lines help to understand the gene expressions, multiple signaling pathways and differential drug responses to HCC. This review article provides insights to the possible molecular pathways involved in the origin of commonly used HCC cell lines and the signals that are functionally active in them. Keywords: hepatocellular carcinoma; malignant; cell lines; molecular pathways; Msignals.