Gene transfer within the cardiovascular system was first demonstrated in 1989 yet, despite extensive basic-science and clinical research, unequivocal benefit in the clinical setting remains to be demonstrated. Potential reasons for this include the fact that recombinant viral vectors, used in the majority of clinical studies, have inherent problems with immunogenicity that are difficult to circumvent. Attention has turned therefore to plasmid vectors, which possess many advantages over viruses in terms of safety and ease of use, and many clinical studies have now been performed using non-viral technology. This review will provide an overview of clinical trials for cardiovascular disease using plasmid vectors, recent developments in plasmid delivery and design, and potential directions for this modality of gene therapy.