Effective delivery of gene therapies to the central nervous system (CNS) is limited by the presence of the blood-brain barrier (BBB). Recently, in murine models, the adeno-associated virus (AAV) vector AAV-PHP.B has demonstrated an ability to overcome this barrier and elicit robust transgene expression throughout the CNS when administered intravenously. AAV-PHP.B achieves this through an engineered receptor interaction with Ly6a, a small GPI-linked protein expressed on the surface of brain microvascular endothelial cells. This AAV-receptor pair provides a model system with a robust phenotype that can be leveraged to better understand the principles of receptor mediated AAV targeting and BBB penetration. To understand the sufficiency of Ly6a targeting and the effects of capsid serotype in conferring BBB penetration, we graft the Ly6a binding epitope from its native AAV9 context into an AAV1 backbone and test the performance of the engineered variants in vivo. We then comprehensively explore the impact of receptor affinity on the systemic targeting and endothelial penetration properties of AAV vectors, using a library of AAV-PHP.B mutants with individually quantitated Ly6a affinities. We find that while Ly6a-targeted AAV9 vectors can efficiently penetrate the BBB, AAV1 vectors targeted to the same receptor primarily establish transduction events in endothelial cells. We also find that AAV9 vectors with high affinity for the Ly6a receptor exhibit substantially reduced BBB penetration, but improved target specificity that evades uptake in liver tissue. Our results demonstrate how the capsid context in which receptor binding is engineered, as well as the receptor affinity conferred by the inserted peptide, can influence the endothelial penetration and systemic targeting properties of AAV vectors. We discuss the implications of these findings for the design and interpretation of AAV library screens, and how these properties can be modulated to obtain precision engineered AAV vectors for specific therapeutic applications.