Reduction/oxidation (redox) regulation mediates numerous cellular responses and contributes to several physiological diseases. The transcription factor nuclear factor kappaB (NF-kappaB) is known to be a redox-sensitive factor. NF-kappaB plays a central role in immune responses and inflammation, through regulation of the gene expression of a large number of cytokines and other immune response genes. NF-kappaB is trapped in the cytoplasm in stimulated cells and translocates into the nucleus in response to several stimuli, including oxidative stress. Reactive oxygen species enhance the signal transduction pathways for NF-kappaB activation in the cytoplasm and translocation into the nucleus. In contrast, the DNA binding activity of oxidized NF-kappaB is significantly diminished, and that activity is restored by reducing enzymes, such as thioredoxin or redox factor 1. This review describes the signal transduction pathways for NF-kappaB activation and redox regulation of NF-kB activation in the cytoplasm and nucleus.