The inhibitor of differentiation or DNA binding (Id) family of transcription regulators plays an important role in cell proliferation, differentiation, and senescence. However, regulation of Id expression during these processes is poorly understood. Id proteins are known to undergo rapid turnover mediated by the ubiquitin-proteasome pathway. Anaphase-promoting complex has been shown to ubiquitinate Id2, but E3 ubiquitin ligase(s) that ubiquitinate other Id family members are not known. Here, we report for the first time the identification of Smurf2 as the E3 ligase that ubiquitinates Id1 and Id3. Smurf2-mediated ubiquitination and consequent degradation of Id1 or Id3 plays an important role in the regulation of Id expression in senescent cells. Furthermore, we found that Id1 is the mediator through which Smurf2 regulates p16 expression, providing a mechanistic link between Smurf2 and p16 expression during senescence.