In vivo gene therapy of human disease using adeno-associated virus (AAV) as a vector has become an established therapeutic modality in the past 6 years. With three approved drugs and a substantial number of Phase 3 clinical trials, the sector is progressing rapidly to taking its place in mainstream medicine. However, critical technological limitations have kept the approach confined to a relatively narrow spectrum of indications thus far. In this Investor Insight, we explore the directions of travel towards the follow-on gene therapies that have the potential to expand the reach of the platform towards broader and more complex indications. We review the ongoing efforts to expand the repertoire of tissues addressable with AAV gene therapy; circumvent the limitations of AAV carrying capacity; and to introduce logic and control mechanisms into in vivo gene therapies. There are two other important factors limiting the use of AAV: the ability to re-administer and manufacturing at scale. These are well reviewed elsewhere and are not the focus of this Investor Insight.