Gene delivery remains the greatest challenge in applying nucleic acid therapeutic for a broad range of diseases. Combining stability during the delivery phase with activation and transgene expression following arrival at the target site requires sophisticated vectors that can discriminate between cell types and respond to target-associated conditions to trigger expression. Efficient intravenous delivery is the greatest single hurdle, with synthetic vectors frequently found to be unstable in the harsh conditions of the bloodstream, and viral vectors often recognized avidly by both the innate and the adaptive immune system. Both types of vectors benefit from coating with hydrophilic polymers. Self-assembling polyelectrolyte non-viral vectors can achieve both steric and lateral stabilization following surface coating, endowing them with much improved systemic circulation properties and better access to disseminated targets; similarly viral vectors can be 'stealthed' and their physical properties modulated by surface coating. Both types of vectors may also have their tropism changed following chemical linkage of novel ligands to the polymer coating. These families of vectors go some way towards realizing the goal of efficient systemic delivery of genes and should find a range of important uses in bringing this still-emerging field to fruition.