Huntington’s disease (HD) is characterized by a significant loss of striatal neurons that project to the globus pallidus and substantia nigra, together with loss of cortical projection neurons in varying regions. Mutant huntingtin is suggested to drive the pathogenesis partially by downregulating corticostriatal brain-derived neurotrophic factor (BDNF) levels and signaling. Neurotrophic factors are endogenous peptides that promote the survival and maintenance of neurons. BDNF and other neurotrophic factors have shown neuroprotective benefits in various animal models of neurodegeneration, and are interesting candidates to protect the cell populations that are destined to die in HD. In an attempt to enhance the delivery of neurotrophic factors, several methods have been established to deliver long-term neurotrophic factor gene therapy to human target tissues. This chapter discusses two alternative approaches that have been shown to have potential to deliver neurotrophic factors as a neuroprotective gene therapy for HD. The methods are (1) ex vivo approach where encapsulated cells engineered to express neurotrophic factor are inserted into brain parenchyma or ventricle, and (2) in vivo viral vector therapy, in which viral vector is injected into desired brain area to express gene of interest in the host cells.