DNA hypermethylation of gene promoters and associated transcriptional silencing can serve as an alternative to mutation for producing loss of tumor suppressor gene function. Some of the classic genes involved and approaches to randomly screen the cancer genome for such gene will be descried, demonstrating their functional role in cancer progression. The study has helped to begin unravel the molecular mechanisms responsible for the initiation and maintenance of the gene silencing, and we plan to utilize all of our findings for translational purposes.