Proper embryonic development and normal tissue homeostasis require a series of molecular processes, regulating cell growth, differentiation and apoptosis. Perturbation in any of these processes invariably contributes to the development of cancer. In particular, defects in apoptosis are seen in virtually all types of human cancers. The Notch pathway plays an important role in cell fate determination in both embryonic development and organ homeostasis. Not surprisingly, Notch also plays a role in cancer when it is dysregulated. In this chapter, we will explore how Notch signaling interacts with key pathways that regulate apoptosis in cancer. Particularly, we will focus on the relationship between Notch and proteins responsible for activation of the caspase pathway. Notch regulates apoptosis through extensive networks, involving cell cycle, growth and survival pathways. Thus, we will also examine how apoptosis is modulated by the crosstalk between Notch and other signaling pathways such as p53, NF-κB and PI3K-Akt pathways.