Notch was first recognized as an important developmental pathway in Drosophila in the first half of the 20th century. Many decades later, this pathway has been found to play central roles in humans in stem cell maintenance, cell fate decisions, and in cancer as well. Notch family members are being revealed as oncogenes in an ever-increasing number of cancers. Though significant progress has been made in dissecting the complex workings of this signaling pathway, there are very limited options available for Notch inhibitors. However, the pioneering class of Notch inhibitors is already in clinical trials for two cancer types. This review will address the current state-of-the-art, agents in the pipeline, and potential strategies for future Notch inhibitors. Successful development of Notch inhibitors in the clinic holds great promise as a new anti-cancer strategy.