RNA interference is now established as an important biological strategy for gene silencing, but its application to mammalian cells has been limited by nonspecific inhibitory effects of long dsRNA on translation. Here, we describe a viral-mediated delivery mechanism that results in specific silencing of targeted genes through expression of small interfering RNA (siRNA). We establish proof of principle by markedly diminishing expression of exogenous and endogenous genes in vitro and in vivo in brain and liver, and further apply this strategy to a model system of a major class of neurodegenerative disorders, the polyglutamine diseases, to show reduced polyglutamine aggregation in cells. This viral-mediated strategy should prove generally useful in reducing expression of target genes to model biological processes or to provide therapy for dominant human diseases.