Simple SummaryPrimary liver tumors impose significant patient morbidity and mortality with overall poor prognosis. To date, conventional therapies have provided only modest survival benefit to patients. Developments in genomics, molecular biomarkers, and artificial intelligence are introducing novel patient-centered approaches to treat primary liver tumors to improve patient survival. Recent FDA-approved immune checkpoint inhibitors Atezolizumab–Bevacizumab and Durvalumab–Tremelimumab have demonstrated improved survival outcomes and in many cases disease downstaging to curative resection. Clinical trials investigating combined immunotherapy and locoregional therapy in advanced liver disease are ongoing with promising preliminary results. Future directions in liver cancer management will likely incorporate treatment algorithms based on individualized patient molecular biomarkers.AbstractPrimary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers.