Molecular therapy is emerging as a potential strategy for the treatment of inflammatory diseases. Decoy oligonucleotides (ONs) against NFkappaB, an inducible transcription factor that plays a critical role in several inflammatory/immune diseases, can specifically block the transcriptional activity of this transcription factor. The therapeutic potential of such decoy ONs has been investigated in several chronic inflammatory-based diseases. However, the clinical use of decoy ONs is strongly hampered by several issues, including low bioavailability, a short half-life and limited intracellular uptake. Both chemical modifications to ONs and the use of delivery systems have been investigated in order to overcome these limitations. This review summarizes the most meaningful studies on the preclinical and clinical application of decoy ONs against NFkappaB in different diseases, and highlights successful strategies that have overcome the pharmacokinetic issues associated with ONs.