Gastrointestinal cancer has now become a leading cause of death in many developed countries and is exceeded only by heart diseases. Although traditional cancer treatments include surgery, chemotherapy, hormone and radiation therapy, alone or in combination, it is still difficult to radically cure patients in the advanced stages of cancer. This is partly due to the diversity and heterogeneity of cancer. The heterogeneity of cancer is reflected by the co-existence of cells with varying differentiation levels in tumors, which affect the efficiency of therapeutics and cause life-threatening metastasis. Recent studies support the notion that small cell populations that mimic normal adult stem cells in the dormant phase of the cell cycle play a role in the biological behavior of tumors. These cancer stem cells are resistant to genotoxic injury and chemoradiation therapy, and they mediate metastasis and recurrence that characterize heterogeneous tumors. Thus, the invention of novel efficient therapies that target these cancer stem cells is required. In this seminar, we summarize recent studies on these cancer stem cells and report two novel approaches. First, the screening of surface markers in dormant gastrointestinal cancer cells that lead to the characterization of chemoresistance and tumorigenicity. By utilizing an outstanding functional marker, CD13/APN, we showed that G0 phase control is abnormal in these cells because of reactive oxygen species (ROS) regulation, and targeting this point could contribute to tumor eradication. Second, with regard to cellular reprogramming, the diversity of these cells is based on complicated mechanisms, including genetic and epigenetic alterations, which produce irreversible and hard-to-control abnormalities. Here, we report an efficient approach to induce cellular reprogramming by the introduction of defined molecules. Our studies established that even cancer cells can be reprogrammed, resulting in increased ES-cell-like gene expression and DNA methylation patterns compatible with iPS/ES cells. This efficient approach could sensitize heterogeneous gastrointestinal cancer cell populations that were largely refractory to chemotherapy and differentiation therapy. Taken together, our study indicates that these novel therapeutic approaches might open an avenue to treat gastrointestinal cancers that are difficult to cure.