Recent advances in understanding the role that epigenetics plays in cancer pathogenesis and understanding the mechanisms through which these processes regulate gene expression have stimulated considerable interest in developing clinically viable antineoplastic agents that target enzymatic components of transcriptional regulatory complexes responsible for the establishment of pathologic epigenetic modifications that lead to deregulated gene expression in cancer. In January 2003, a workshop was held in Baltimore to discuss the therapeutic potential of several agents that can modify chromatin structure. A follow-up meeting on "Clinical Translation of Epigenetics in Cancer" was held in Charleston, SC, in January 2005. The aim of this workshop was to assess the progress that has been made over the past 2 years in bringing effective therapeutic protocols that use agents capable of reverting pathologic epigenetic changes into the clinic. The meeting was attended by approximately 70 investigators and included formal presentations, panel group discussions, and two break-out sessions that addressed targeted therapies in hematologic and solid tumors. The aim of this article is to summarize topics discussed at this workshop and highlight conclusions as to the immediate and long-term future of epigenetic therapy in cancer.