Understanding the mechanism of tumor recurrence after radiotherapy is important in achieving disease-free survival in cancer patients. Radiation-triggered nuclear factor kappa B maintains a self-sustenance mechanism through a positive feed-back cycle. Persistent activation of NF-kB imparts survival advantage to the cancer cells that survive treatment through selective downstream determinants. Thus favorably selected cancer cells undergo clonal expansion resulting in tumor promotion/progression at the treatment site. Molecular targeting of radiation-induced NF-kB feed-back axis could prevent tumor recurrence and improve the quality of life of cancer patients.