The notch/STAT3-Ser/Hes3 signaling axis is a recently identified signal transduction branch of the notch signaling pathway, originally shown to regulate the number of neural stem cells in culture and in the living adult brain. Pharmacological activation of this pathway opposed the progression of neurodegenerative disease in rodent models. More recent efforts have implicated it in carcinogenesis and diabetes. The pathway can be activated by soluble ligands of the notch receptor which induce the sequential activation of intracellular kinases and the subsequent phosphorylation of STAT3 on the serine residue at amino acid position 727 (STAT3-Ser). This modification is followed by an increase in the levels of Hes3, a transcription factor belonging to the Hes/Hey family of genes (see HES1). Hes3 has been used as a biomarker to identify putative endogenous stem cells in tissues. The pathway is an example of non-canonical signaling as it represents a new branch of a previously established signaling pathway (notch). Several efforts are currently aimed at relating this pathway to other signaling pathways and to manipulate it in a therapeutic context.