The expansion of CAG repeats within the coding region of associated genes is responsible for nine inherited neurodegenerative disorders including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and dentatorubral-pallidoluysian atrophy (DRPLA). Despite years of research aimed at developing an effective method of treatment, these diseases remain incurable and only their symptoms are controlled. The purpose of this study was to develop effective and allele-selective genetic tools for silencing the expression of mutated genes containing expanded CAG repeats. Here we show that repeat-targeting short hairpin RNAs preferentially reduce the levels of mutant huntingtin, atrophin-1, ataxin-3, and ataxin-7 proteins in patient-derived fibroblasts and may serve as universal allele-selective reagents for polyglutamine (polyQ) diseases.