This chapter provides an in-depth discussion of the signaling pathways frequently implicated in the pathogenesis of liver cancer, particularly hepatocellular carcinoma (HCC), and the inhibitors targeting these pathways that are under investigation or already in use for advanced liver cancer management. It highlights the oncogenic roles of these pathways and the current state of research on inhibitors, with a focus on tyrosine kinase inhibitors (TKIs) due to their limited clinical application and resistance issues. The chapter also emphasizes the need for innovative targeted strategies to overcome existing limitations and improve patient outcomes in advanced liver cancer. Key signaling pathways discussed include growth factor receptor-related pathways (VEGF, FGF, TGF-β, EGFR, IGF, c-Met, PDGF), downstream receptor tyrosine kinase pathways (Ras/Raf/MEK/ERK, PI3K/AKT/mTOR), and growth factor receptor-independent pathways (Wnt-β-catenin, JAK/STAT, Hedgehog, Hippo, Notch, NF-κB). The chapter underscores the importance of understanding these pathways for developing more effective targeted therapies.This chapter provides an in-depth discussion of the signaling pathways frequently implicated in the pathogenesis of liver cancer, particularly hepatocellular carcinoma (HCC), and the inhibitors targeting these pathways that are under investigation or already in use for advanced liver cancer management. It highlights the oncogenic roles of these pathways and the current state of research on inhibitors, with a focus on tyrosine kinase inhibitors (TKIs) due to their limited clinical application and resistance issues. The chapter also emphasizes the need for innovative targeted strategies to overcome existing limitations and improve patient outcomes in advanced liver cancer. Key signaling pathways discussed include growth factor receptor-related pathways (VEGF, FGF, TGF-β, EGFR, IGF, c-Met, PDGF), downstream receptor tyrosine kinase pathways (Ras/Raf/MEK/ERK, PI3K/AKT/mTOR), and growth factor receptor-independent pathways (Wnt-β-catenin, JAK/STAT, Hedgehog, Hippo, Notch, NF-κB). The chapter underscores the importance of understanding these pathways for developing more effective targeted therapies.