Although the global genetic elimination of Htt described herein differs from the clinical trial paradigm, in which the aim is to lower (and not eliminate) Htt expression specifically in the brain in the context of HD, the extensive behavioral and pathological deficits that we observed in our gene-inactivation paradigm still caution against the use of non-allele specific gene expression silencing strategies, and indicate that therapies targeting specifically the mutant Htt allele in HD patients [68–71] might represent a safer alternative. This evidence concerns the gene HTT and Huntington disease.