Profound changes in the epigenetic landscape of cancer cells underlie the development of human malignancies. These changes include large-scale DNA methylation changes throughout the genome as well as alterations in the compendium of post-translational chromatin modifications. Epigenetic aberrations impact multiple steps during tumorigenesis, ultimately promoting the selection of neoplastic cells with increasing pathogenicity. Identification of these alterations for use as predictive and prognostic biomarkers has been a highly sought after goal. Recent advances in the field have not only greatly expanded our knowledge of the epigenetic changes driving neoplasia but also demonstrated their significant clinical utility as cancer biomarkers. These biomarkers have proved to be useful for identifying patients whose malignancies are sensitive to specific cytotoxic chemotherapies and may hold promise for predicting which patients will benefit from newer targeted agents directed at oncogenes. The recent application of global analysis strategies has further accelerated our understanding of the epigenome and promises to enhance the identification of epigenomic programs underlying cancer progression and treatment response.