Huntington's disease (HD) is caused by an expansion of CAG triplets at the 5′ end of the HD gene, which encodes a pathologically elongated polyglutamine stretch near the N-terminus of huntingtin. HD is an incurable autosomal-dominant neurodegenerative disease characterized by movement disorder, as well as emotional distress and dementia. The newly discovered roles of the non-coding small RNAs in specific degradation or translational suppression of the targeted mRNAs suggest a potential therapeutic approach of post-transcriptional gene silencing that targets the underlying disease etiology rather than the downstream pathological consequences. From pre-clinical trials in different HD animal models to cells from HD patients, small RNA interference has been applied to ‘allele-non-specifically or allele-specifically’ silence the mutant HD transgene or endogenous mutant HD allele. Silencing the mutant HD transgene significantly inhibits neurodegeneration, improves motor control, and extends survival of HD mice. With future improvement of mutant allele selectivity (preserving the expression of the neuroprotective wild-type allele), target specificity, efficacy and safety, as well as optimization of delivery methods, small non-coding RNA-based therapeutic applications will be a promising approach to treat HD.