DNA-based cancer vaccines represent an attractive strategy for inducing immunity to tumor associated antigens (TAAs) in cancer patients. The demonstration that the delivery of a recombinant plasmid encoding epitopes can lead to epitope production, processing, and presentation to CD8+ T-lymphocytes, and the advantage of using a single DNA construct encoding multiple epitopes of one or more TAAs to elicit a broad spectrum of cytotoxic T-lymphocytes has encouraged the development of a variety of strategies aimed at increasing immunogenicity of TAA polyepitope DNA-based vaccines. The polyepitope DNA-based cancer vaccine approach can (a) circumvent the variability of peptide presentation by tumor cells, (b) allow the introduction in the plasmid construct of multiple immunogenic epitopes including heteroclitic epitope versions, and (c) permit to enroll patients with different major histocompatibility complex (MHC) haplotypes. This review will discuss the rationale for using the TAA polyepitope DNA-based vaccination strategy and recent results corroborating the usefulness of DNA encoding polyepitope vaccines as a potential tool for cancer therapy.