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Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling. We found that Dl requires ubi for its full function, but can also signal in two ubi-independent modes, one dependent and one independent of Neur. We identified two neural lateral specification processes where Dl signals in an ubi-independent manner. Neur, which is needed for these processes, was shown to be able to activate Dl in an ubi-independent manner. Our analysis suggests that one important role of DSL protein ubi by Mib1 is their release from cis-inhibitory interactions with Notch, enabling them to trans-activate Notch on adjacent cells., eLife digest Cells use chemical signals to communicate, setting off chains of reactions known as signalling pathways. One key signalling pathway, thought to be required for the development of all animals, is called Notch. In fruit flies, signal proteins known as Delta and Serrate activate the Notch pathway by binding to receptors on the outside of the cell. To do so, the signal proteins first need to be activated themselves. Two enzymes known as Mindbomb1 and Neuralized activate Delta and Serrate. Both enzymes add a small unit called ubiquitin to specific locations on the signal proteins, but the effect that ubiquitin has on Notch signalling is not yet fully understood. Berndt, Seib, Kim et al. have now examined fruit flies that had a variety of genetic mutations. These included some flies that could produce mutant versions of the Serrate and Delta proteins that lacked the locations to which ubiquitin normally attaches. The results of the experiments reveal that Delta requires ubiquitin, Mindbomb1 and Neuralized to work at full capacity. However, Delta could still perform some of its roles without ubiquitin. Neuralized and Delta can partner up to send some signals independently of ubiquitin, and Delta can even send some signals on its own. Serrate, on the other hand, does not work at all without ubiquitin. The results presented by Berndt et al. help us to understand the role that ubiquitin plays in activating Notch signalling. Further work that builds on these findings could help to shed light on how uncontrolled Notch activation can contribute to a variety of diseases, including cancer, cardiovascular diseases and multiple sclerosis.