The protein Numb localizes to clathrin-coated vesicles and participates in the trafficking of transmembrane receptors. Numb is a protein whose asymmetric segregation during cell division determines cell fate and has numerous functions relevant to multiple fields of study, including developmental neurobiology and cancer biology. Numb serves as a key regulator of Notch and Sonic Hedgehog signaling and also modulates p53 protein levels. Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment.