Over the past 10 years, genetic therapies for neurologic diseases have advanced rapidly. Genetic therapies are well situated to directly modify pathogenesis due to a single gene or a complex neurodegenerative disease (NDD) arising from a single (or small number of) pathogenic proteins. Despite this potential, there has been little clinical translation due to our inability to efficiently and safely deliver genes to the brain. Intra-arterial delivery (IA) can potentially deliver genes to the brain safely. Yet, few studies have investigated IA delivery. This chapter will provide an in-depth literature review, focusing on IA delivery of gene therapies for NDDs involving the brain. We will provide recommendations for future directions for preclinical and clinical gene delivery research, hoping to turn this theoretical strategy into a practical reality.