Cells in multicellular organisms need to decipher extracellular cues into appropriate responses including correct differentiation choices. A considerable portion of this information is relayed through a surprisingly small number of signaling pathways, which are highly evolutionarily conserved and used in many different cell types. This “ivy league” of signaling mechanisms comprises the Wnt/wingless, BMP/TGF-beta, Sonic Hedgehog, receptor tyrosine kinases, nuclear receptors, JAK/STAT and, the subject of this review, the Notch signaling pathway. The aim of this article is to provide an overview of the Notch signaling pathway. The role of Notch in various types of cancers is discussed in the accompanying articles in this issue of SCBI.