The use of DNA as a drug is both appealing and simple in concept. Indeed in many instances the feasibility of such an approach has been established using model systems. In practical terms, however, the delivery of DNA to human tissues presents a wide variety of problems that differ with each potential therapeutic application. In this review, the design, production, and application of viral vectors for human gene therapy are considered. Although viral vectors are an obvious starting point because viruses have evolved efficient mechanisms to introduce and express their nucleic acid into recipient cells, by the same token the viral hosts have evolved sophisticated mechanisms to rid themselves of such pathogens. The challenge for the therapeutic use of viral vectors is to achieve efficient and often extended expression of the exogenous gene while evading the host defenses. Methodology used and progress towards that goal are reviewed.