Although modern biotechnology has produced extremely sophisticated and potent drugs, many of these compounds cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of skin. Because the primary barrier to transport is located in the upper 10-15 micron of skin and nerves are found only in deeper tissue, we used a reactive ion etching microfabrication technique to make arrays of microneedles long enough to cross the permeability barrier but not so long that they stimulate nerves, thereby potentially causing no pain. These microneedle arrays could be easily inserted into skin without breaking and were shown to increase permeability of human skin in vitro to a model drug, calcein, by up to 4 orders of magnitude. Limited tests on human subjects indicated that microneedles were reported as painless. This paper describes the first published study on the use of microfabricated microneedles to enhance drug delivery across skin.