The selective loss of neurons in Huntington's disease (HD) is caused by the abnormal expansion of the CAG triplet (>36 repeats) of the HD gene. Although the molecular events that lead to neuronal death are not clear, it is most likely that mutant HD protein operates through a “gain‐of‐function” mechanism. One possible therapeutic approach that does not require definition of the toxic mechanism(s) involves reduction in the levels of mutant HD protein by decreasing the quantity of translatable HD mRNA. In this report, we demonstrate the first effective destruction of the HD mRNA, using a catalytic DNA—an oligodeoxynucleotide with RNA‐cleaving enzymatic activity. We show that the cleavage of HD mRNA by the catalytic DNA occurs in a sequence‐specific manner, and leads to significant reduction of HD protein expression in mammalian cells. The catalytic DNAs we have developed are a valuable research tool for studying HD, and may have the therapeutic potential of reducing cellular toxicity caused by mutant HD protein.