Regulation of the humanIGF2gene displays multiple layers of control, which secures a genetically and epigenetically predetermined gene expression pattern throughout embryonal growth and postnatal life. These predominantly nuclear regulatory mechanisms converge on the function of theIGF2-H19gene cluster on Chromosome 11 and ultimately affectIGF2gene expression. Deregulation of such control checkpoints leads to the enhancement ofIGF2gene transcription and/or transcript stabilization, ultimately leading to IGF-II peptide overproduction. This type of anomaly is responsible for the effects observed in terms of both abnormal fetal growth and increased cell proliferation, typically observed in pediatric overgrowth syndromes and cancer. We performed a review of relevant experimental work on the mechanisms affecting the humanIGF2gene at the epigenetic, transcriptional and transcript regulatory levels. The result of our work, indeed, provides a wider and diversified scenario forIGF2gene activation than previously envisioned by shedding new light on its extended regulation. Overall, we focused on the functional integration between the epigenetic and genetic machinery driving its overexpression in overgrowth syndromes and malignancy, independently of the underlying presence of loss of imprinting (LOI). The molecular landscape provided at last strengthens the role ofIGF2in cancer initiation, progression and malignant phenotype maintenance. Finally, this review suggests potential actionable targets forIGF2gene- and regulatory protein target-degradation therapies.