The Notch signalling pathway is an evolutionary conserved mechanism that regulates many cell-fate decisions. In the canonical pathway, the binding of ligands to Notch at the cell surface activates this transmembrane protein by releasing an intracellular domain from it, which translocates to the nucleus where it acts as a co-activator for the DNA-binding protein Suppressor of Hairless, Su(H). Hori and colleagues now describe how Deltex (Dx) – a Drosophila E3 ubiquitin ligase – positively regulates Notch signalling in the wing imaginal disc in a Su(H)-independent manner (see p. 5527). By examining a series of fly mutants, the researchers show that Notch movement from the cell surface to the late endosome requires Dx, and that this translocation is essential for Dx-mediated activation of Su(H)-independent Notch signalling. Thus, they conclude, two distinct signalling pathways downstream of a single receptor are uniquely activated in different membrane-bound compartments.