Organisms have four Notch receptors (Notch 1-4) that are bipartite, single-pass transmembrane proteins composed of a large extracellular domain noncovalently linked to a smaller transmembrane and intracellular domain. Activation of Notch receptors requires direct cell-cell interactions between the extracellular portion of the receptor and transmembrane ligands of the Jagged and Delta/Serrate/Lag-2 (DSL) families. Additional integral membrane, GPI-linked, and secreted proteins have also been reported to be Notch ligands. Notch activation results in the sequential proteolysis of Notch by TNF-converting enzyme (TACE/ADAM17) and Presenilin-dependent gamma-secretase. These cleavage events promote the release of the Notch intracellular domain, which translocates to the nucleus to regulate the transcription of Notch target genes. Notch signaling is highly conserved in multicellular organisms and is important for specifying cell fates, regulating pattern formation, and defining boundaries between different cell types during early development. It is required for multiple developmental processes, including vasculogenesis, angiogenesis, hematopoiesis, somatogenesis, myogenesis, and neurogenesis and has been implicated in cancer biology.