Recent studies in gene transfer suggest that the innate immune system plays a significant role in impeding gene therapy. In this review, we examine factors that might influence the recruitment and activation of the innate system in the context of gene therapy. We have adopted a novel model of immunology that contends that the immune system distinguishes not between self and nonself, but between what is dangerous and what is not dangerous. In taking this perspective, we provide an alternative and complementary insight into some of the failures and successes of current gene therapy protocols.