DLL4 is a ligand for the Notch family of receptors. DLL4 has many important functions in normal development and tissue homeostasis, including roles in the immune system, the gastro-intestinal tract, and in vascular development. Because of the importance of Notch signaling in stem cell biology, DLL4 has been investigated for its role in the maintenance and proliferation of cancer stem cells (CSC). In addition, its important role in angiogenesis has been investigated for utility as an anti-angiogenic agent. Preclinical studies have highlighted that both anti-CSC and anti-angiogenic activities contribute to its anti-tumor efficacy, and have supported the clinical development of anti-DLL4 antibody for the treatment of cancer.