AS WE APPROACH the new millennium, a quick glance backwards reveals that truly astounding progress has been made in the identification of genes responsible for cell growth, development, and neoplastic transformation. With this knowledge has come a natural desire to ‘‘translate’’this information into new therapeutic strategies for many of the common maladies that afflict humankind. These include in particular cardiovascular, gastrointestinal, neurologic, infectious, and neoplastic diseases. Attempts at inserting genes into cells that either replace, or counter the effects of, diseasecausing genes has been one of the primary ways in which scientists have tried to exploit this new knowledge. This technically complex, as yet largely unrealized endeavor1, 2 is what most individuals think of when the terms ‘‘gene therapy’’or ‘‘molecular medicine’’are discussed. Nevertheless, alternative strategies for treating diseases at the gene level are being developed. The common goal of these various strategies, which are turning out to be as technically demanding as more traditional gene therapy, is to identify disease related genes and target them for ‘‘silencing.’’Because the numbers of maladies that might be treated by this approach are genuinely enormous, this is clearly a most important field of endeavor. It will be the goal of this review to describe available strategies for ‘‘silencing,’’or perhaps more appropriately, perturbing gene expression. Given the expertise and experience of our laboratory, we will place special emphasis on the use of reverse complementary or so called ‘‘antisense’’oligodeoxynucleotides (ODN) for this purpose. Problems associated with the use of antisense ODN for modifying gene expression are well known and they will be discussed, along with potential strategies for overcoming these problems. The prospects for ultimately using these materials successfully in the clinic will also be elaborated upon. This review is meant to be complete, but not exhaustive. Even a cursory examination of the literature data base reveals that since 1992 more than 1,300 manuscripts have been published which list antisense DNA or RNA among its key words. We therefore apologize in advance to colleagues whose work we do not cite, but which we nonetheless admire.