The Notch signaling system is a well-preserved developmental signaling mechanism that plays an essential role in regulating tissue balance and cell destiny during embryonic development. Anomalies in Notch signaling have been associated with the pathogenesis of various diseases, such as cancer. We shall describe the mechanism and control of the Notch signaling system in this chapter. We will also discuss the part Notch signaling plays in the initiation, progression, and development of cancer. In order to demonstrate the mechanics, contributions to physiological development, associated disorders, and therapeutic uses of the NOTCH pathway, we will concentrate on both traditional and contemporary research concerning NOTCH signaling. We anticipate that this chapter will aid both novices and professionals in developing a methodical and in-depth understanding of the NOTCH signaling pathway in cancer.