Hypermethylation of CpG islands, an epigenetic event that is not accompanied by changes in DNA sequence, represents an alternative mechanism to deletions or mutations to inactivate tumor suppressor genes. Recent evidence supports the notion that CpG island hypermethylation, by silencing key cancer-related genes, plays a major causal role in cancer. However, a long-standing issue in the field is the sequence of molecular events leading to epigenetic gene silencing. A new model has been proposed that chromatin remodeling, as a result of histone deacetylation and methylation, is the primary event in abrogating transcriptional initiation; subsequently, CpG island hypermethylation establishes a permanent state of gene silencing. Accumulating evidence indicates that CpG island hypermethylation is an early event in cancer development and, in some cases, may precede the neoplastic process. Because of their heritable nature, hypermethylated CpG islands leave 'molecular footprints' in evolving cancer cells and can be used as molecular markers to reconstruct epigenetic progression during tumorigenesis. Furthermore, hypermethylated CpG islands are proving to be useful for molecular classification of different cancer types.