Hepatocellular carcinoma (HCC) remains a major global health burden, and therapeutic resistance continues to limit the benefit from systemic treatment. Despite advances in systemic therapies, including immune checkpoint inhibitor-based combinations, antiangiogenic agents, and multitargeted tyrosine kinase inhibitors for patients with advanced HCC, primary non-response and acquired resistance are common. This review summarizes the mechanisms that underlie resistance to contemporary HCC therapies, including tumour heterogeneity, molecular pathway rewiring and crosstalk, tumour microenvironment and immune escape, epigenetic alterations, epithelial-to-mesenchymal transition, and cancer stem cell expansion. We discuss how these mechanisms limit the efficacy of current doublet and triplet regimens, and why biologically rational combinations do not consistently translate into clinical benefit. Emerging strategies to overcome resistance, including biomarker-enriched trial designs and liquid biopsy are also discussed. A deeper integration of mechanistic insights with translational biomarkers will be essential to improve treatment durability and clinical outcomes for patients with HCC.