Recent studies have identified an increasing number of genes that are inactivated by promoter region methylation in cancer. Some of these genes were initially identified as altered genetically in cancer, but in other tumors they are silenced in associationwith promoter region CpG island methylation. New approaches for screening the genome add to this list of candidatetumor suppressor genes, and many genes regulated key pathways in cancer, including cell cycle control, DNA repair, andapoptosis. Transcription factors may also be silenced by promoter region methylation, affecting the expression of manydownstream target genes and globally altering the cancer phenotype. Determining loss of expression is important in assigningfunctional importance to promoter region methylation for any gene. Individual cancers have alterations in many differentgenes, affecting many of these important pathways and contributing to the cancer phenotype. The number of genes targetedfor promoter region methylation increases during neoplastic progression. These studies suggest that the epigeneticchange of promoter region methylation plays a critical role in neoplastic transformation and progression.