Cell transformation is strictly linked to important metabolic changes which are instrumental for initial survival of cancer cells and subsequent spreading of disease. Early (i.e., anerobic glycolysis) and late metabolic changes (i.e., fatty acid metabolism) are required for progression and clinical emergence of cancer. Besides well-known tumor suppressors and oncogenes, several metabolic genes have been found implicated in this multistep process, among which are fatty acid synthase (FASN) and carnitine palmitoyl transferase I (CPT I). An intriguing link between these metabolic shifts and a change in the balance between nuclear and secreted forms of CLU (nCLU/sCLU) has been suggested. The shifting balance between CLU forms during tumor progression, by affecting the fate of the cell, seems to be strongly influenced by the metabolic shift occurring in the different steps of tumor progression.