Along with the elucidation of the role of cytotoxic T lymphocytes in the immune responses against a number of pathogens and cancer, and with the increased understanding of the cellular processing mechanisms of antigens for generation of these cells, has come an increased focus on vaccines that can generate cellular immunity along with antibodies. Promising approaches based on the delivery of genes, either as plasmid DNA or by viral vectors, have been extensively evaluated pre-clinically and in early-phase clinical trials. Although the first generation of DNA plasmid vaccines were broadly effective in animal disease models, early clinical immunogenicity pointed towards the need for increased potency. This manuscript reviews recent developments for gene-based vaccines, specifically, new approaches for formulating and delivering plasmid DNA and alphaviral replicon vectors, all of which have resulted in increased potency of gene-based vaccines.