It has become apparent that epigenetically mediated alterations, which establish heritable abnormalities in gene expression, are a fundamental feature of human cancer. The best studied of these changes are aberrant gene silencing events which involve transcriptional inactivation associated with abnormally methylated promoter region CpG islands. A most important aspect of understanding this change, which can cause loss of key gene function, concerns dissection of the molecular mechanisms that mediate the transcriptional repression and those responsible for establishing the abnormal methylation and associated chromatin events. This chapter reviews the progress in these arenas.