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.