The Notch signaling pathway appears to be responsible for maintaining a balance between cell proliferation and apoptosis and thus it has been suggested that Notch may play an important role in species development and in the development and progression of several malignancies. Therefore, the Notch signaling pathway may represent a novel therapeutic target, which could have the highest therapeutic impact in modern medicine. This review describes the mechanisms of signal transduction of the Notch signaling pathway and provides emerging evidence in support of its role in the development of human malignancies. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch signaling, which could become a novel approach for cancer prevention and treatment.