Changes in the levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington disease, Alzheimer disease and Parkinson disease. It is only in Huntington disease, however, that gain-of-function and loss-of-function experiments have linked BDNF mechanistically with the underlying genetic defect. Altogether, these studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. In this article, we will review the current knowledge about the involvement of BDNF in a number of neurodegenerative diseases, with particular emphasis on Huntington disease, and will provide the rationale for and discuss the problems in proposing BDNF treatment as a beneficial and feasible therapeutic approach in the clinic.