Advances in molecular virology, and in understanding the molecular basis of human disease, has led to intensive efforts to use viruses for delivering therapeutic genes to cells. Although gene therapy (GT) to treat disease is still in its infancy, the techniques developed for gene delivery to cells have become more sophisticated, and are useful in a variety of experimental settings. This chapter focuses on two viral systems: adenovirus (AD) and herpes simplex virus (HSV)-based vectors. AD represents a nonenveloped DNA virus with a well-characterized genome. Vectors have been developed that are reasonably nontoxic and easy to manipulate in the laboratory. HSV vectors are enveloped viruses with a large and well-characterized DNA genome. Nontoxic variants of this virus have also been developed. Although Ad and HSV vectors share some basic features, there are also significant differences in the types of cells that they infect. This chapter focuses on HSV amplicons, which are essentially plasmids packaged into a HSV shell, and on replication-defective Ad.