The incidence and mortality of liver cancer, mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), are increasing rapidly worldwide. Diverse risk factors for primary liver cancer have been identified, including infection of hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol abuse and non-alcoholic steatohepatitis (NASH) as well as intake of aflatoxin B1. Consistent with the complex and multifactorial etiologies, multi-omics analyses of human HCC and ICC samples have identified vast genomic heterogeneity, molecular and cellular defects, metabolic reprogramming, and subtypes of tumors as well as altered tumor microenvironment in the liver. However, it remains to be determined if any common molecular signatures in the transcriptomes exist for liver cancer, despite their considerable genomic heterogeneity. Furthermore, little is known about the kinetics and fashions, either gradual accumulation or dramatic transition, in generation of cell-intrinsic and -extrinsic signals that are intertwined to drive malignant transformation of hepatocytes and tumor initiation.