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Five decades ago nucleic acids were transfected by precipitation with cationic polymers [1].Since the report of asialoglycoprotein receptor-mediated in vivo gene transfer in 1988 by George and Catherine Wu [2],our understanding of polymers and their rational use in gene delivery has gradually increased.The recognition of the biological challenges in extra-and intracellular delivery without triggering toxicity triggered several breakthrough developments,including surface-shielded polyplexes,polymers with endosomal escape properties,and biodegradable polymers.Despite a better understanding,significant challenges such as nuclear defivery and persistence of gene expression remain.Biologically,high resolution microscopy and bioimaging strongly support our insight on involved delivery mechanisms.Improved precision in macromolecular chemistry enables better design of polymeric carriers.The therapeutic perspectives have widened from pDNA based gene therapy to application of various novel therapeutic nucleic acids including siRNA and microRNA.Medical efficacy still remains to be demonstrated.