Gene therapy strategies aimed at restoring dopaminergic function by either expressing genes that encode enzymes responsible for synthesis of dopamine (DA) or expressing growth factors capable of improving DA function in the degenerated neurons have the potential to halt the progression of Parkinson’s disease (PD). Glial cell line–derived neurotrophic factor (GDNF), in particular, has disease-modifying therapeutic potential due to demonstrated roles in improving DA neuronal survival and growth in preclinical studies. Early attempts to ameliorate symptoms of PD using recombinant GDNF protein delivered to the brains of patients showed promise; however, these studies were limited by inadequate delivery strategies, off-target effects of GDNF, and suboptimal pharmacokinetics and generally targeted patients with too advanced disease. In this chapter, we address these important issues and put them into the context of data that have been obtained from current and recent clinical trials. We then explain how these historical challenges have contributed to the development of the current GDNF gene therapy delivery strategy that seeks to overcome these issues.