Nuclear factor-kappa B (NF-kappa B) is a signal transcription factor that has emerged as an important modulator of altered gene programs and malignant phenotype in development of cancer. Major carcinogens and oncogenic viruses induce NF-kappa B activation, and a variety of subsequent oncogenic events contribute to a progressive increase in constitutive NF-kappa B activation as an important common pathway in most forms of cancer. NF-kappa B target genes promote tumor cell proliferation, survival, migration, inflammation, and angiogenesis. Inhibition of NF-kappa B has been found to be an important mechanism of action of steroids, nonsteroidal anti-inflammatory drugs, and natural and synthetic compounds that show therapeutic and preventive activity. Newer agents targeting the proteasome, inhibitor-kappa B kinase, and other upstream kinases involved in NF-kappa B activation have shown anticancer activity in clinical or preclinical studies.