Notch signaling is an important molecular pathway involved in the determination of cell fate. In recent years, this signaling has been frequently reported to play a critical role in maintaining progenitor/stem cell population as well as a balance between cell proliferation, differentiation and apoptosis. Thus, Notch signaling may be mechanistically involved carcinogenesis. Indeed, many studies have showed that Notch signaling is overexpressed or constitutively activated in many cancers including colorectal cancer (CRC). Consequently, inactivation of Notch signaling may constitute a novel molecular therapy for cancer. CRC is one of the most common malignancies but the current therapeutic approaches for advanced CRC are less efficient. Thus, novel therapeutic approaches are badly needed. In this review article, the authors reviewed the current understanding and research findings of the role of Notch signaling in CRC and discussed the possible Notch-targeting approaches in CRC.