DNA hypermethylation in CpG-rich promoters is now recognized as a common feature of human neoplasia. However, the pathophysiology of hyper-methylation (why, when, where) remains obscure. Cancers can be classified according to their degree of methylation, and those cancers with high degrees of methylation (the CpG island methylator phenotype, or CIMP) represent a clinically and aetiologically distinct group that is characterized by 'epigenetic instability'. Furthermore, CIMP-associated cancers seem to have a distinct epidemiology, a distinct histology, distinct precursor lesions and distinct molecular features.