Transcription factors belonging to the NF-kappaB superfamily are involved in several human pathologies, as well as in biological processes facilitating the onset of diseases. Among well established functions of NF-kappa B factors is the promotion of osteoclast differentiation in osteopenic diseases, the enhancement of inflammatory processes in cystic fibrosis, the involvement in asthma and pulmonary diseases associated to dust or smoke. In consideration of these roles of NF-kappaB, targeting of these transcription factors could be of great interest. A very promising approach to alter NFkappaB regulated gene expression is the transcription factor decoy (TFD) strategy. The TFD approach employs double stranded oligodeoxyribonucleic acids mimicking the NF-kappaB binding sites or bioactive analogues; therefore, treatment of cells with these decoy molecules causes a binding of NF-kappaB factors to them and not to the target promoter sequences, leading to a strong inhibition of NF-kappaB dependent biological functions. Decoy molecules targeting NFkappaB factors were found in vitro inducers of apoptosis, and strong inhibitors of cell cycle progression, and TNF-alpha induced gene expression in several experimental cell systems. In vivo, decoy molecules targeting NF-kappaB factors were employed for prolonged survival of renal allografts, regression of atopic dermatitis, and cardiac protective effects. Therefore, the design and development of novel molecules able to target NF-kappaB, including modified oligonucleotides, LNA (locked nucleic acids) and peptide nucleic acids (PNA) based transcription factors decoys are of great interest. In this respect, TFD activity of double stranded PNA-DNA-PNA chimeras has been demonstrated to be useful to inhibit NF-kappaB dependent functions.