Antisense oligodeoxynucleotide compounds (AS ODN) are being developed as therapeutics for various disease indications. Their safety and pharmacokinetics are most commonly evaluated in rodents and nonhuman primates. Traditional AS ODN are short, single strands of DNA, and they target specific mRNA sequences. Plasma clearance of AS ODN is rapid, broad tissue distribution occurs, and elimination is by nuclease metabolism. Structural modifications to AS ODN have been made to enhance their efficacy and improve their safety. A number of class effects are observed with AS ODN that are unrelated to the specific targeted mRNA sequence. Acute effects include activation of the alternative complement pathway and inhibition of the intrinsic coagulation pathway. In monkeys, rodents, and dogs given repeated doses of AS ODN, accumulation of AS ODN and/or metabolites occurs in the form of basophilic granules in various tissues, including the kidney, lymph nodes and liver. A new potential therapeutic application of ODN is that of immune stimulation. Immunostimulatory ODN (IS ODN) are being investigated for use in treating cancer, infectious disease, and allergy. For the development of both AS and IS ODN, primates will continue to be important for safety assessment.