For more than three decades, plasmids have been widely used in the biotechnology arena. Historically, they have been most often employed for the expression of heterologous proteins in a variety of microorganisms. More recently, plasmids have been used as vectors for the delivery of antigen encoding genes in order to elicit immune responses in higher order animals. In this chapter, we discuss methods for constructing vectors with this unique purpose. Considerations for choosing the replicon, antigen, expression elements, and host cells are discussed within the context of developing a commercially viable vaccine vector.