Imprinting is defined as the parental allele-specific expression of a very limited set of genes (about 50–80). This regulation depends upon an epigenetic marking of parental alleles during gametogenesis. Monoallelic expression ensures that the levels of the proteins encoded by imprinted genes, important factors of embryonic growth, placental growth or adult metabolism, are assured. Without precise control of their expression, developmental abnormalities result, as is shown by a number of hereditary over-growth syndromes, including Beckwith–Wiedemann syndrome. The regulation of imprinted genes is largely dependent on methylation marks, which are laid down during embryological development of germ cells. Once in place, the methylation status of precise chromosomal regions, Imprinting Control Regions (ICRs), is read by either of two mechanisms, chromatin barrier formation or untranslated RNAs, thereby ensuring that only the maternal or paternal allele is expressed. Each imprinted gene is classified as maternal or paternal according to the expressed allele. The stability of the marked regions in somatic cells is maintained through each cellular replication by a methylation enzyme complex containing Dnmt1. Although the major reading mechanisms of imprinted status are known, chromatin boundary formation by CTCF and untranslated RNAs, the molecules elaborating the initial ICR methylation, are just being uncovered. Mis-regulation of imprinted gene expression (loss of imprinting [LOI]) is seen frequently and precociously in a large variety of human tumours, making LOI a potentially valuable tool for both diagnosis and treatment. In fact, LOI is presently considered the most abundant and most precocious alteration in cancer. The present review proposes a mechanism responsible for LOI, as well as its eventual value in tumour diagnosis and prognosis. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.