Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder marked by chorea, dystonia, incoordination, and cognitive and motor disturbance. The major cause of HD is the cytotoxicity of the mutant huntingtin protein (mHTT), encoded by the mutant HTT gene. The mechanism by which mHTT leads to cytotoxicity and neuronal death is unclear, and thus enhancing clearance of the mHTT protein is likely to be an effective approach to treat HD. We have recently identified NUB1 (negative regulator of ubiquitin-like proteins 1) as a modifier of mHTT levels via enhancement of its proteasomal degradation. In this review, we will discuss the mechanism of NUB1-mediated mHTT clearance and potential targeting strategies.