Recombinant Adeno-associated viral vectors (rAAVs) are the leading platform for in-vivo gene therapy. Despite many desirable properties, rAAVs have several limitations that prevent their application to many diseases, and their difficulty to manufacture at large scales earned rAAVs the title "The Most Expensive Drug in the World." Although rAAV vectors have been studied for nearly 40 years, the adeno-associated virus (AAV) from which they originate causes no disease; therefore AAV interactions with host cells are historically understudied and remain poorly defined. Understanding the basic biology at the interface of rAAV and its host cell is the first step to illuminate how these mechanisms can be tuned to overcome rAAV's clinical limitations. In this talk, I will present my graduate work studying AAV capsid assembly, how I applied these findings to identify key structure-function relationships within the icosahedral capsid, and how I used these principles to engineer capsids that assemble without a previously required viral co-factor. Next, I will share my postdoctoral work that identified host factors involved in processing rAAV-delivered DNA, and how their manipulation led to an over 30-fold increase in expression of an oversized transgene. Finally, I will summarize the plans for my future lab, which will continue studying vector-host interactions to overcome major limitations in the rAAV gene therapy field.