Hepatocellular carcinoma (HCC) corresponds to the vast majority of liver cancer cases, with one of the highest mortality rates. Major advances have been made in this field both in the characterization of the molecular pathogenesis and in the development of systemic therapies. Despite these achievements, biomarkers and more efficient treatments are still needed to improve its management. Heparan sulfate (HS) chains are polysaccharides that are present at the cell surface or in the extracellular matrix that are able to bind various types of molecules, such as soluble factors, affecting their availability and thus their effects, or to contribute to interactions that position cells in their environments. Enzymes can modify HS chains after their synthesis, thus changing their properties. Numerous studies have shown HS-related proteins to be key actors that are associated with cellular effects, such as tumor growth, invasion, and metastasis, including in the context of liver carcinogenesis. The aim of this review is to provide a comprehensive overview of the biology of HS chains and their potential importance in HCC, from biological considerations to clinical development, and the identification of biomarkers, as well as therapeutic perspectives.