A frequent concern in the diagnosis of colon cancer is to select the most reliable biomarkers for the prediction of malignancy of tumor cells as well as the use of these markers as potential molecular targets to improve response to therapy. Cancer stem cell-like population or tumor-initiating cells (TICs) are thought to be a sub-population of malignant cells that vary according to tumor subtype and histologic stage in cancer. TICs have also been proposed as predictors for therapy resistance and, therefore, an inferior prognosis. However, very little research has been conducted to explore the roles of TIC markers during the process of tumor initiation and progression. Signaling pathways activated by TIC markers such as the transcription factors c-Myc, Nanog, Oct4, and Sox2 activate pathways are very important components of the machinery that maintains the pluripotency in both embryos and stem cells. These pluripotent genes are frequently overexpressed in tumor cells that are poorly differentiated compared with those well differentiated. Certain surface markers associated with stem cells such as CD24, CD44, and CD133 have also been indicated as strong markers for TICs in several types of tumors. The altered expression of TIC markers during the tumorigenesis process is of vital importance for the development of therapies. This approach ultimately will target TICs that are refractory to a giving treatment, leading to tumor recurrence. This review discusses the potential applications of TIC markers that may predict risk of clinical outcome and provide a guide for appropriate therapy in colorectal carcinomas.