Hedgehog pathway is crucial for the maintenance and self-renewal of neural stem cells and for tumorigenesis. Hedgehog signaling is limited by multiple E3 ubiquitin ligases that process the downstream transcription factors Gli. Cullin family-based ubiquitination results in either Cullin1-Slimb/betaTrCP- or Cullin3-HIB/Roadkill/SPOP-dependent proteolytic processing or degradation of Drosophila Cubitus interruptus or mammalian Gli proteins. We have recently identified Itch as an additional HECT family E3 ligase, able to ubiquitinate and degrade Gli1. A functional link with the influence of Hedgehog signaling on cell development and tumorigenesis is suggested by the identification of Numb as a promoter of such an Itch-dependent ubiquitination process that leads to Gli1 degradation, thus suppressing its transcriptional function. Numb is an evolutionary conserved developmental protein that, during progenitor division, asymmetrically segregates to daughter cells thereby determining distinct binary cell fates. Numb is downregulated in cerebellar progenitors and their malignant derivatives (i.e. medulloblastoma cells). Furthermore, Numb has anti-proliferative and pro-differentiation effects on both cerebellar progenitors and medulloblastoma cells, due to its suppression of functional Gli1. These findings unveil a novel Numb/Itch-dependent regulatory loop that limits the extent and duration of Hedgehog signaling during neural progenitor differentiation. Its subversion emerges as a relevant event in brain tumorigenesis.