The incidence of hepatocellular carcinoma (HCC) is increasing. Dysregulated metabolism is an important contributor to the pathogenesis of cancer. Experimental models suggest that impeding glucose production promotes HCC. The role of liver glycine N-methyltransferase (GNMT) in the relationship between glucose control and HCC is of particular interest. GNMT-null mice develop HCC by eight months of age, suggesting a causal role in tumorigenesis. Hughey et al. studied the relationship of GNMT action and glucose production to HCC formation. The results show that the lack of GNMT reduces glucose production. Reduced glucose production is coupled to impaired NAD+ synthesis and salvage. A decline in NAD+ availability may redirect the flux of glucose precursors to pathways that regulate tumorigenesis.