Since the 1960s, serum alpha-fetoprotein (AFP) quantification combined with radiographic imaging has constituted the diagnostic cornerstone, with this paradigm remaining essentially unchanged for over six decades; however, AFP’s role as a “gold standard” predictor, the role of AFP continues to be highly controversial because of its limited specificity and the ambiguous biology behind the connection between AFP and HCC. This evidence concerns the gene AFP and hepatocellular carcinoma.