The Notch pathway powerfully influences stem cell maintenance, development and cell fate and is increasingly recognized for the key roles it plays in cancer. Notch promotes cell survival, angiogenesis and treatment resistance in numerous cancers, making it a promising target for cancer therapy. It also crosstalks with other critical oncogenes, providing a means to affect numerous signaling pathways with one intervention. While the gamma-secretase inhibitors are the only form of Notch inhibitors in clinical trials, other forms of Notch inhibition have been developed or are theoretically feasible. In this chapter we review the rationales for Notch inhibition in cancer and then discuss in detail the various modalities for Notch inhibition, both current and speculative.