Vectors based on recombinant adeno-associated virus (AAV) 2/8 hold considerable promise for use in human gene therapy. These vectors are safe, and have minimal immunostimulatory properties. Their combination with efficient, liver-specific promoters allows high-level transgene expression in the hepatocytes of small and large animals. In small animal models, this high level of liver expression results in tolerance to the transgene products. Tolerance to transgene products may also be achievable using these vectors for human gene therapy, but the HLA diversity (and thus variability in T cell recognition of transgene products) and high frequency of prior natural exposure to AAV in human populations impose additional challenges that must be overcome in order for this strategy to succeed.