Sepsis, a syndrome that occurs when microbial invasion induces systemic illness, is one of the most common reasons for critical ill patients to be admitted to an intensive care unit and, despite advances in overall medical care, it represents a major clinical problem and remains the leading cause of death in the critically ill patient population. A major hurdle in the clinical management of patients suffering from the sepsis syndrome is the lack of the effective treatment. Thus, the important goal in critical care medicine is to find out significant therapeutic strategies that would impact favorably on patient outcome. Gene therapy can be considered as one of the most promising novel therapeutic approaches for nasty disorders. Since sepsis can be characterized by the induction of multiple genes and their products, sepsis may be regarded as a gene-related disorder. A number of transcription factors, including NF-kB, AP-1 and STAT3, are profoundly activated during sepsis, and may play a pivotal role in the pathophysiology of sepsis. The decoy strategy has been developed as a useful tool for the involvement of those transcription factors in disease pathology. The decoy oligodeoxynucleotides (ODNs) can specifically compete for the binding elements of those transcription factors, thereby blocking their actions. We have devised the potential usefulness of different transcription factor ODNs for gene therapy of sepsis. Our results suggest that the development of decoy ODN techniques for those transcription factors may provide new perspectives on revolutionary gene-therapy approaches for the fight against sepsis.