Viral vectors have different capabilities as gene delivery vehicles for vaccines and immunotherapeutics. This review discusses selected viral vector systems and plasmid DNA and provides an overview of their specific characteristics, strengths, and limitations. The features, modes of viral entry and replication, expression of heterologous proteins, issues related to both preexisting and heterologous immunity, and vaccine strategies are discussed for the different vectors. Comparisons of the features and capabilities of the vectors are provided.