The nuclear factor-kappa B (NF-kappaB) plays a critical role in regulating expression of genes responsible for a wide range of cellular processes, including innate and adoptive immune responses, and pathways related to cell survival and proliferation. Based on its property as a transcription factor, NF-kappaB has been considered as a good target for the treatment of inflammatory immune diseases. To regulate gene expression, "decoy" oligodeoxynucleotides (ODNs) are ideal tools to interfere with binding of transcription factors to promoter regions in genes. Herein we review the application of NF-kappaB decoy ODNs to control inflammatory disorders and transplantation tolerance. In addition, we provide information about induction of antigen-specific peripheral tolerance by their topical application. Regulation of NF-kappaB signaling by NF-kappaB decoy ODNs might be an effective tool to control a variety of disorders caused by inflammatory immune responses.