Over the last few years, hydrodynamic tail vein delivery has established itself as a simple, yet very effective method for gene transfer into small rodents. Hydrodynamic delivery of plasmid DNA expression vectors or small interfering RNA allows for a broad range of in vivo experiments, including the testing of regulatory elements, antibody generation, evaluation of gene therapy approaches, basic biology and disease model creation (non-heritable transgenics). The recent development of the hydrodynamic limb vein procedure provides a safe nucleic acid delivery technique with equally high efficiency in small and large research animals and, importantly, the prospects for clinical translation.