The Notch pathway is highly conserved and has a wide range of physiological roles including regulating cell fate, proliferation, angiogenesis, cell survival, and the immune response. Aberrant Notch activity may also have complex and context-dependent effects on tumorigenesis. Notch receptors (Notch-1, -2, -3, -4) and ligands exist as type-1 transmembrane proteins. In mammals, canonical Notch ligands include members of the Delta-like (DLL) and Jagged families. Upon ligand binding, the Notch receptor is proteolytically cleaved in a stepwise manner, releasing the Notch intracellular domain (NICD) into the cytosol where it translocates to the nucleus. In the absence of the NICD, the DNA binding protein CSL/RBPj acts as a transcriptional repressor in complex with a range of putative co-repressors, linker proteins, and enzymes. In the nucleus, the NICD binds CSL/RBPj and Mastermind-like (MAML), recruiting transcriptional co-activators and forming a complex that induces the transcription of Notch target genes. The activity and turnover of the NICD may be regulated by ubiquitination and phosphorylation. It is the balance between the activities of the opposing regulators that dictate the level of overall Notch activity. Adding to the complexity of the Notch pathway, it is becoming increasingly evident that Notch can signal via non-canonical means. For instance non-canonical ligands have been identified that may activate or suppress Notch signaling depending on the context. There is also crosstalk between Notch and other signaling pathways and molecules, including Akt/TOR, NF-kappa B, beta-Catenin, and others.