The first in vivo adeno-associated viral vector (AAV) gene transfer experiments were performed in murine models of muscle directed gene transfer. These studies were remarkable for stable expression of a variety of immunogenic transgenes. These findings were translated to other target organs with multiple therapeutic gene products. Technological improvements and the lessons learned from basic research have heralded an era of first-in-human clinical trials. In most settings, AAV appears to evade host immune surveillance, allowing the delivery of robust levels of genetic cargo that leads to persistent expression. However, in few experimental settings immunological responses raised following AAV mediated gene transfer have compromised vector efficacy. Parameters that determine these occurrences have been proposed to be pre-existing immunity to AAV, the route of administration, the kinetics of expression, the dose, the vector serotype and its ability to transduce antigen-presenting cells (APCs) as well as the host species and nature of the specific transgene product. Overall, the underlying mechanisms remain the topic of scientific debate. This review aims to compile, confront and critically discuss the findings in which AAV appears to be an immunogen.