Gene therapy research is still in trouble owing to a paucity of acceptable vector systems to deliver nucleic acids to patients for therapy. Viral vectors are efficient but may be too dangerous for routine clinical use. Synthetic non-viral vectors are inherently much safer but are currently not efficient enough to be clinically viable. The solution for gene therapy lies with improved synthetic non-viral vectors based upon well-found platform technologies and a thorough understanding of the barriers to efficient gene delivery and expression (transfection) relevant to clinical applications of interest. Here we introduce and interpret synthetic non-viral vector systems through the ABCD nanoparticle structural paradigm that represents, in our view, an appropriate lens through which to view all synthetic, non-viral vector systems applicable to in vitro use or in vivo applications and gene therapy. Our intention in introducing this paradigm is to shift the focus of organic and physical chemists away from the design of yet another cytofectin, and instead encourage them to appreciate the wider challenges presented by the need to produce tool kits of meaningful chemical components from which to assemble viable, tailor-made nanoparticles for in vivo applications and gene therapy, both now and in the future. © 2005 Elsevier Inc. All rights reserved.