Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy that commonly arises in the setting of chronic liver disease and cirrhosis. Despite advances in surveillance, diagnostics, and therapeutics, HCC remains challenging to manage due to late-stage detection, high recurrence rates, and pronounced molecular and immune heterogeneity. Dysregulated pathways including WNT/β-catenin and PI3K/AKT/mTOR and immunosuppressive mechanisms involving programmed death ligand-1 and transforming growth factor-beta contribute to treatment resistance and variable clinical outcomes. Although molecularly targeted therapies and immunotherapies have improved survival, their benefits are not uniform across patient subgroups, reflecting the biological diversity of HCC. These interindividual differences underscore the need for precision medicine approaches that integrate genomic profiling, liquid biopsy, multiomics analyses, and biomarker-driven treatment selection. In this chapter, we highlight the molecular drivers, immune landscape, heterogeneity, and emerging precision-guided therapeutic strategies that are reshaping the clinical management of HCC.