As widely reported, the efficacy of metformin as anti-cancer compound is mainly exerted by the following mechanisms, schematically represented in Figure 2: (1) decrease of blood glucose and insulin levels; (2) activation of AMPK and LKB1; (3) inhibition of mTOR signaling; (4) cell cycle arrest; (5) apoptosis and autophagy triggered by p53 and p21; (6) stop of protein synthesis; (7) immune system activation; (8) cancer stem cell destruction; (9) inhibition of unfolded protein response (UPR); (10) diminution of hyperlipidemia; (11) angiogenesis prevention [15]. This evidence concerns the gene TP53 and cancer.