The safe and efficient delivery of therapeutic DNA to cells represents a fundamental obstacle to the clinical success of gene therapy. The challenges facing synthetic delivery vectors are particularly clear, as both cationic polymers and liposomes are less effective at mediating gene transfer than viruses. We have developed a high-throughput parallel approach to synthesize libraries of hundreds to thousands of cationic polymers and identify new gene delivery agents through rapid cell-based screening assays. We are extending this approach using various polymerization mechanisms to include new structural motifs and functional groups for discovery-based screening and optimization of vectors across multiple cell and tissue types. With an emphasis on rapid elucidation of structure-activity relationships for new classes of polymeric vectors, we hope to accelerate the rate at which new materials are identified for clinical applications.