Hepatobiliary cancer refers to primary malignant tumors originating in cells of the liver, bile ducts, and gallbladder. Globally, primary liver cancer, which includes hepatocellular carcinoma ( 75 % of all cases) and intrahepatic biliary cancer or cholangiocarcinoma ( 10-15 % 0f all cases) is the 6th most commonly diagnosed cancer and 3rd leading cause of cancer deaths worldwide. The vast majority of these highly malignant cancers are diagnosed at an advanced stage where treatment options are limited and patient survival outcomes are poor. The biological and therapeutic challenges posed by hepatobililiary cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are daunting, emphasizing a critical need to review and assess current and evolving basic, translational, and clinical research focused on addressing the critical obstacles that continue to limit progress towards achieving significant improvements in HCC and CCA clinical management and patient survival outcomes. Towards this goal, this special edition of Advances in Cancer Research is focused on providing a comprehensive, timely and authoritative reviews covering such topics of significant scientific and clinical relevance, including hepatobiliary cancer risk mechanisms and risk-predictive molecular biomarkers; causes and functional intricacies of inter- and intratumor heterogeneity; novel insights into the role of tumor microenvironment and key signaling pathways in promoting hepatobiliary cancer progression, therapeutic resistance and immunosuppression; emerging biomarkers of HCC and CCA prognosis; advances in molecular genomics for personalizing tumor classification and targeted therapies; innovative preclinical cell culture modeling for hepatobiliary cancer drug discovery; and current and emerging trends in hepatobiliary cancer molecular therapeutic targeting and immunotherapies.