Cancer is a major cause of death worldwide. Gastrointestinal (GI) cancers are still an important cause of tumor-related deaths. Conventional therapeutic approaches like surgery, chemotherapy, and radiation therapy are indispensable but insufficient. Despite the advances in immunotherapy and other conventional treatment strategies, some might argue that we are still far from curing cancer. Cancer stem cells (CSCs) might be to blame. Because sequencing technologies are moving fast in this precision-medicine era, molecular testing of tumors, circulating tumor cells, and CSCs have important implications for treatment decisions. Biomarkers offer prognostic values and targeted therapy availabilities as molecular predictive factors. CSCs are considered biomarkers of tumorigenesis development, metastasis, and recurrence. In this review, we summarize the important issues over CSCs and the development of new drugs that target GI CSCs.