Walt Lima and colleagues report the design of single-stranded small interfering RNAs (ss-siRNAs) that effectively silence targeted mRNAs in animals (Cell 150, 883–894, 2012). These ss-siRNAs have a modified, metabolically stable 5′ phosphate and can activate RNA interference (RNAi) in vitro and in mice. In the same issue, David Corey and colleagues, in collaboration with Walt Lima and colleagues, report the development of ss-siRNAs that can specifically inhibit a mutant huntingtin allele (Hdh) in mice (Cell 150, 895–908, 2012). Huntington disease is caused by the expansion of CAG trinucleotide repeats within the gene that encodes huntingtin (HTT). No effective drugs have been developed for this disease, and work to date has suggested that it may be effective to develop allele-specific inhibitors that only reduce mutant and not wild-type HTT. To this end, Corey and colleagues used systematic chemical modifications and iterative design to develop ss-siRNAs with ribose modifications and a 5′ end that is capped with (E)-vinyl phosphate. They found that an optimized ss-siRNA was capable of inhibiting mutant HTT in a fibroblast cell line derived from an individual with Huntington disease. They then showed that intraventricular delivery of a particular ss-siRNA could inhibit mutant HTT in a heterozygous mouse (HdhQ150/Q7) carrying a knock-in allele with 150 CAG repeats in exon 1.