Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation.