Although the leading dogma for the origin of the diversity in cancer cell subpopulations is based on a stepwise selection and accumulation of genetic changes that allow uncontrollable malignant growth, there is an emerging understanding that the variability of heritable phenotypes in cancer and cancer-prone cells may also involve epigenetic mechanisms. This is exemplified by the unscheduled activation of the normally repressed maternal IGF2 allele in a wide range of human cancers. The notion that this so-called loss of imprinting (LOI) provides a proliferative advantage by increasing the levels of the IGF-2 ligand available to its receptors is supported by the overgrowth symptoms of neonatal mice, which has been genetically manipulated to express Igf2 biallelically. Although the mechanisms underlying IGF2 LOI in human cancer remains unknown, it is likely to directly or indirectly involve the H19 imprinting control region (ICR). This stretch of 2 kb sequence just upstream of the H19 promoter functions to block enhancer-Igf2 promoter communications by means of a DNA methylation-sensitive chromatin insulator. We discuss here the possibility that pathological mechanisms leading to IGF2 LOI use different strategies with the neutralization of the H19 ICR insulator function as a common denominator.