Glutamine Synthetase (GS) catalyzes the synthesis of glutamine, which is the major energy source of tumor cells. Accumulation of GS was first found through analyzing increased ubiquitinated protein in hepatocellular carcinoma (HCC) and its stepwise increase in expression from precancerous lesions to early advanced HCC. Liver biopsy for HCC detection is largely restricted to small hepatocellular lesions, which are often morphologically challenging, requiring careful distinction between dysplastic nodules (high-grade) and well-differentiated HCC. When a panel of GS, Heat Shock Protein 70 and Glypican 3 is used, if any 2 of the 3 are positive, the sensitivity and specificity for the detection of early and HCC-G1 were 72% and 100% respectively. Also GS activity is a marker for astrocytes and can be used to distinguish astrocytic from oligodendroglial tumors and may play a role in the pathogenesis of astrocytomas.