The ubiquitin-proteasome system (UPS) regulates many cellular processes, including protein stability, cell cycle control, DNA repair, transcription, signal transduction, and protein trafficking. In fact, UPS plays a key role in various stress conditions such as ischemia, glutamate toxicity, Alzheimer’s disease, and Parkinson’s disease. Huwe1, a homologous to E6-AP carboxy terminus (HECT) domain ubiquitin ligase, is now being regarded as a vital protein involved in neural stem cell differentiation, adult neurogenesis, and the DNA damage response pathway. In response to DNA damage, Huwe1 may have a dual function in arresting DNA replication and in ending checkpoint signaling. The proliferation and differentiation of neural stem cells regulated by Huwe1-mediated Notch signaling could also play an important role in neural protection following neural injury. Considering Huwe1 is required for neural precursor survival and the regulation of the DNA damage response pathway, there is growing evidence and considerable hope that Huwe1 might be a therapeutic target for neural injury.