Gene therapy, the ability to treat a disease at the level of nucleic acid, has journeyed from science fiction, to hard lessons learned from early clinical trials, to improved technologies with efficacy in patients for several diseases. Adeno-associated virus (AAV) vectors are currently a leader for direct in vivo gene therapy. To date, AAV is safe in patients, with clinical benefit in trials to treat blindness, hemophilia, and a lipid disorder, with many more trials underway. Despite this remarkable progress, barriers exist for AAV vectors to be effective gene transfer vehicles in all organ/cell targets, as well as patient subpopulations. Extracellular vesicles (EVs, e.g., exosomes, microvesicles) are natural lipid particles released by many cell types. They have been reported to mediate cell to cell communication via transferred contents including proteins, nucleic acids, and metabolites. These properties of EV attracted our attention to help solve certain gene transfer issues encountered by AAV vectors. We made the initial discovery that a subpopulation of AAV vectors isolated from media directly interacted with EVs [referred to as exosome-associated AAV (exo-AAV)]. In following reports, we have demonstrated that exo-AAV has advantages over the conventional AAV vector in areas such as anti-AAV antibody evasion and transduction of cells of the eye and cochlea in preclinical models. The work of others using EVs as therapeutics as well as our continued development of the exo-AAV platform may advance the field towards useful clinical applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.