Double-stranded oligodeoxynucleotides (ODN) containing the consensus binding sequence of a transcription factor are valuable tools for the manipulation of gene expression at the transcriptional level by means of the decoy strategy. The approach involves flooding the cells with enough ODN decoy to compete for binding of the transcription factor with its consensus sequence in target genes. The technique has been proven effective in vitro and in vivo, suggesting its use in therapy. Therefore, great attention has been recently focused on chemical modifications enhancing biostability of the oligonucleotides so as to improve their pharmacological properties. Unfortunately, benefits in terms of nuclease resistance have been often negated by a decrease in the affinity and / or specificity of transcription factor binding. To circumvent these problems, circular dumbbell and chimeric decoy oligonucleotides, the latter comprising a central stretch of transcription factor recruiting deoxynucleotides flanked by modified nucleotides, have been introduced. Nevertheless, these approaches have the limitation of leaving the ODNs still sensitive to endonuclease cleavage. To address these concerns, we have recently investigated the use of a new class of nucleotide analogs termed locked nucleic acids (LNA) in the designing of decoy molecules for the transcription factor κB (NF-κB). In this article, we review the advantages of LNA in the design of ODN decoys pointing to the feasibility of introducing modifications in the transcription factor binding sequence in order to obtain molecules with increased stability compared to end-capped ODNs, while remaining efficiently recognized by NF-κB.