The structure and order existing among various chemical interactions characterizing life are ultimately controlled by the genetic material encoded in DNA. DNA sends out information periodically to control all cellular processes. Thc complex nature of gene expression both in prokaryotes and eukaryotes involves multiple DNA regulatory proteins which either selectively activate or repress specific nucleic acid sequences (1-3). A novel form of genetic regulation in prokaryotes whereby a specific messenger RNA's translation was suppressed by its hybridization or binding to an antisense RNA (4.5) led to the antisense approach for regulation of gene expression. Newer technologies to synthesize complex organic molecules enabled large-scale production of antisense oligonucleotides and demonstrated their efficacy in vitro (2, 6, 7), a concept proposed as early as 1967 (8). For successful therapeutic use of these compounds, their stability, target specificity, and pharmacokinetic profile must be established as favorable (9). Numerous studies have identified the optimal ph ysicochemical characteristics of antisense oligonucleotides in vitro (2.10-21). In vivo data regarding pharmacokinetics and toxicity, however, have been few. This paper describes in vivo pharmacokinetic and toxicological properties of synthetic antisense oligonucleotides. Oligonucleotide structures have been modified to increase stability and resist endo-and exonuclease degradation by the following processes: