Advancements in programmable DNA-Binding Proteins (DBDs) that target the genome,such as zinc fingers, transcription activator-like effectors, and Cas9, have broadened drug targetdesign beyond traditional protein substrates. Effective delivery methodologies remain a major barrierin targeting the central nervous system. Currently, adeno-associated virus is the most wellvalidateddelivery system for the delivery of DBDs towards the central nervous with multiple, ongoingclinical trials. While effective in transducing neuronal cells, viral delivery systems for DBDsremain problematic due to inherent viral packaging limits or immune responses that hinder translationalpotential. Direct administration of DBDs or encapsulation in lipid nanoparticles may providealternative means towards delivering gene therapies into the central nervous system. This reviewwill evaluate the strengths and limitations of current DBD delivery strategies in vivo. Furthermore,this review will discuss the use of adult stem cells as a putative delivery vehicle for DBDs and thepotential advantages that these systems have over previous methodologies.