The recent approval of azacitidine (Vidaza®), decitabine (Dacogen®) and vorinostat (Zolinza™) for myelodysplastic syndrome and cutaneous T-cell lymphoma has led to a wave of interest in epigenetic therapy. These DNA methylation inhibitors and the histone deacetylase inhibitor clearly have demonstrated activity in hematologic malignancies, but the future role of epigenetic therapy in solid tumors is still unknown. What is not commonly known is that azacitidine and decitabine were originally developed as cytotoxic nucleoside analogs and clinical trials were previously conducted in a variety of cancer types prior to the knowledge of their ability to inhibit DNA methylation. We review the experience of azacitidine and decitabine in early clinical trials and demonstrate the activity of epigenetic therapy in solid tumors.