Polyglutamine diseases are a group of neurodegenerative disorders characterized by the expansion of a CAG trinucleotide in a protein-coding gene. The translation of these expanded repeats leads to long polyglutamine tracts that increase the potential of the protein to aggregate itself and other proteins into the pathological amyloid conformation. Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia 3, is the second most common polyglutamine disease behind Huntington disease. In MJD, the CAG expansion occurs in the ATXN3 gene. Currently there are no FDA-approved therapies to prevent or cure MJD. However, RNA-based therapies that silence the expression of or alter the structure of the mutant protein have the potential to prevent and ameliorate the disease. Here, we will review how RNA interference (RNAi) and antisense oligonucleotides (AONs) could potentially be used to target ATXN3. These technologies could mediate allele-specific silencing of mutant ATXN3 alleles but also allele non-specific silencing for individuals without a targetable polymorphism. Both RNAi and AONs could be used to promote mRNA degradation and translational inhibition; in addition AONs may be used as splicing modulators. The evidence suggests that viral-mediated delivery of RNAi therapies may have longer term potency than liposomal-mediated delivery of RNAi or AON therapies; however, this has not been fully explored in animal models. Nevertheless, there are promising results from studies of MJD and similar neurodegenerative disorders that suggest that RNAi and AON technology may be a viable long-term treatment therapy.