Although the genetic and epigenetic mechanisms underlying IGF2 expression in cancer have been reviewed elsewhere [[28], ibidem] and are not the subject of the present perspective, we included this mechanism as an example of the role of TP53 in the regulation of IGFBP-3, which is directly involved in the high-affinity binding of mature IGF-I and IGF-II but not of cancer-secreted big-IGF-II. The gene discussed is IGFBP3; the disease is cancer.