Synthetic oligodeoxynucleotides (ODN) capable of “neutralizing” or “inhibiting” immune responses have been described. This review will focus on the properties of phosphorothioate ODN that mimic the immunosuppressive activity of the repetitive TTAGGG motifs present in mammalian telomeres. These TTAGGG multimers block the production of pro-inflammatory and T helper type 1 cytokines elicited when immune cells are activated by a wide variety of Toll-like receptor ligands, polyclonal activators, and antigens. Several mechanisms contribute to the suppressive activity of such ODN. Ongoing microarray studies indicate that suppressive ODN interfere with the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT4, thereby blocking the inflammation mediated by STAT-associated signaling cascades. In animal models, suppressive ODN can be used to prevent or treat diseases characterized by persistent immune activation, including collagen-induced arthritis, inflammatory arthritis, systemic lupus erythematosus, silicosis, and toxic shock. These findings suggest that TTAGGG multimers may find broad use in the treatment of diseases characterized by over-exuberant/persistent immune activation.