Glycosylation of cell surface proteins regulate critical cellular functions including migration, growth, proliferation, adhesion and apoptosis. Tumorigenic cells possess gene mutations that alter glycosylation enzyme and substrate quantities resulting in glycosylation changes on the surface of the malignant cell. This may lead to metastasis, uncontrolled proliferation and the inhibition of apoptosis all of which are the hallmarks of cancer. The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide, and as a consequence there is a need for improved diagnostic, prognostic and treatment strategies. Currently, the diagnosis of HCC utilises specific glycosylation markers in the serum of patients; however, the efficacy of diagnosis would be further enhanced by including cancer stem cell-specific and novel HCC-associated glycosylation markers. Their application will facilitate earlier, more sensitive diagnoses and reliable staging of the cancer leading to a more effective treatment.