Huntington's disease (HD) is an autosomal dominant hereditary disease caused by a trinucleotide repeat mutation in the huntingtin gene that results in an increased number of glutamine residues in the N terminus of huntingtin protein. Mutant huntingtin leads to progressive impairment of motor function, cognitive dysfunction, and neuropsychiatric disturbance. There are no disease-modifying treatments available. During the past decade, sirtuin-1 (SIRT1) has been the focus of intense investigation and discussion because it regulates longevity in multiple organisms and has shown beneficial effects in a variety of models of neurodegenerative disorders. Studies in different animal models provide convincing evidence that SIRT1 protects neurons in mouse models of HD as well as in Caenorhabditis elegans, although controversial results were reported in a fly model. Indeed, many connections exist between the deacetylation function of SIRT1 and its role in neuroprotection. As a result, pharmacological interventions targeting SIRT1 might become promising strategies to combat HD. This review summarizes recent progress in SIRT1 research, with a focus on the specificity of this protein as a potential therapeutic target for HD, as well as existing challenges for developing SIRT1 modulators for clinical use.