Innate and acquired chemoresistance exhibited by most tumors exposed to conventional chemotherapeutic agents account for most relapse cases in cancer patients . In addition to multiple key well-known molecular players, lncRNAs have been shown to be involved in the development of chemoresistance . Most recently, Manel Esteller's group has discovered the lncRNA – TP53TG1 as a chemo-sensitizer to promote p53 response to DNA damage (Figure 1B) . By comparing DNA methylation profiles of colon cancer cell line HCT-116 with or without disrupted DNA methyltransferase enzymes, along with normal colon cell line, the authors have identified a dozen of lncRNAs which exhibited CpG island hypermethylation-associated transcriptional silencing in colon cancer cells. In normal colon tissues, the p53 protein binds the regulatory region of the TP53TG1 molecule and activates it in response to cellular stress . Thereafter, TP53TG1 blocks activation of the YBX1 protein that, when induced, goes into the cell nucleus and stimulates many oncogenes . 10% of colon and stomach tumors show inactivation of the TP53TG1 molecule due to hypermethylation at CpG island, furthermore, oncology patients with inactive TP53TG1 have a shorter progression-free survival . TP53TG1 silencing in cancer cells causes the p53 protein to lose its antitumor effects and free the RNA binding protein YBX1 to activate oncogenes that prevent the death of malignant cells in response to anti-tumor drugs, resulting in chemoresistance . Of course, YBX1 should not be the only ‘hit’ resulting from the epigenetic loss of TP53TG1 in the center p53 link. Alternative targets would warrant further research. Esteller's lab and others have underscored that epigenetic factors are highly associated with multi-resistance of tumors to most common drugs, although it remains unclear how these epigenetic mutations occur in tumor cells.