Cancer is a disease of the genome. Whereas efforts to understand the molecular basis of cancer have in the past largely focused on the role of mutations, recent evidence points to a strong epigenetic component in tumorigenesis, and epigenetic defects have been linked to loss of cell cycle control and cell survival. Here, we discuss the possibility that epigenetic alterations may promote tumor formation by an alternative mechanism. We speculate that epigenetic changes in stem cells and somatic cells contribute significantly to carcinogenesis by disruption of cellular differentiation programs. Epigenetic interference and loss of cellular identity may be particularly relevant for the emergence of cancer stem cells.