Due to their capacity for inducing strong and sequence specific gene silencing in cells, small interfering RNAs (siRNAs) are now recognized not only as powerful experimental tools for basic research in Molecular biology but with promising potentials in therapeutic development. Delivery is a bottleneck in many studies. There is a common opinion that full potential of siRNA as therapeutic agent will not be attained until better methodologies for its targeted intracellular delivery to cells and tissues are developed. Electropulsation (EP) is one of the physical methods successfully used to transfer siRNA into living cells in vitro and in vivo. This review will describe how siRNA electrotransfer obeys characterized biophysical processes (cell-size-dependent electropermeabilization, electrophoretic drag) with a strong control of a low loss of viability. Protocols can be easily adjusted by a proper setting of the electrical parameters and pulsing buffers. EP can be easily directly applied on animals. Preclinical studies showed that electropermeabilization brings a direct cytoplasmic distribution of siRNA and an efficient silencing of the targeted protein expression. EP appears as a promising tool for clinical applications of gene silencing. A panel of successful trials will be given.