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In 2012 there were 11,957,599 advanced cancer cases in the US reported by CDC and the incidence has been almost unchanged over the previous 8 years (482,000 cases in 2000 versus 456,000 cases in 2008). There has been an annual percentage change of only (-0.6) between years 1999 to 2008 in cancer incidence. It is well described in the recent literature that epigenetic alterations are at least if not more important than genetic defects for the development and progression of malignant diseases. In the therapeutic field, transcriptional therapy is a very promising form of cancer treatment that is being extensively evaluated. It is speculated that inhibitors of DNA methylation and histone deacetylases can reactivate expression of tumor suppressor genes and induce histone hyperacetylation in the tumors of patients with solid cancers after treatment with these agents. Hypermethylation and transcription silencing of suppressor genes has been shown in 33% of breast cancers, 60% of prostate CA and 92% of colon CA. Although the value of such combination therapy both in chemoprevention, as well as treatment in patients with cancer is extremely important and can cause a significant shift in the current practice of oncology and cancer prevention, unfortunately, the results in clinical studies have been poor as the target histone hyperacetylation does not correlate with survival ( possibly due to P 16/21 resistance and unselectiveness of the conventional therapies/targets). Here this synergism is shown to be clinically relevant in a set of cases treated with a combination of epigenetic modifiers, using off label and natural therapies in a protocol called Multi targeted epigenetic therapy ( MTET), using non toxic natural substances currently tested in preclinical studies of cell cultures with preliminary results confirming apoptosis. Clinical application of such method of treating cancer has caused promising preliminary results. Here we present the summary of outcomes in thirty cases of advanced cancer with three cases, described in detail, that were treated through this method. We conclude that further research is warranted in a larger spectrum and clinical trial setting to evaluate the efficacy of such method.