Epigenetic silencing of gene transcription by methylation of DNA or modification of histones is a key event in neoplastic initiation and progression. Alterations of the epigenome have been identified in virtually all types of cancer and involve multiple genes and molecular pathways. Recent studies have suggested that epigenetic gene inactivation may represent the first step in tumorigenesis, possibly by affecting the normal differentiation of stem cells and by predisposing these cells to additional oncogenic insults. The mechanisms that drive epigenetic silencing in pre-malignant cells are still unknown, but may reflect simple stochastic events that are beneficial to cancer precursor cells. It is now well established that epigenetically silenced genes may be reactivated pharmacologically. Some inhibitors of DNA methyltransferases (5-aza-cytidine and 5-aza-2'-deoxycytidine) or histone deacetylases (vorinostat) have been approved for clinical use by the US Food and Drug Administration and have reached clinical phase III trials elsewhere. The prospect that epigenetic alterations may play an essential role in renewing and maintaining the malignant clone has opened up new perspectives for the use of epigenetic therapy in cancer prevention and maintenance.