NF-κB is a transcriptional factor which is involved in many biological processes including immunity, inflammation, and cell survival. Many investigators studied on the mechanism involved in activation of NF-κB signalling pathway via ubiquitination and degradation of IkB. Recently, termination of NF-κB signaling after activation is regarded as another essential regulating step. In addition to the negative feedback by IkB protein, ubiquitination and degradation of nuclear p65/RelA, a crucial subunit of NF-κB, is considered another mechanism to terminate the NF-κB signaling. COMMD1, PDLIM2, GCN5 and NMRAL1 are recently reported as proteins related with p65/ RelA ubiquitination. Interestingly, ubiquitination and degradation of p65/RelA through viral protein was also found in the process of viral infection to escape from host defence mechanism. In contrast with somatic cells, expression of NF-κB is relatively low in undifferentiated embryonic stem (ES) cells, and activity of NF-κB is down-regulated by Nanog via direct interaction. Furthermore, enforced expression of NF-κB resulted in differentiation suggesting that down regulation of NF-κB contributes to the maintenance of ES cells. Therefore, better understanding on the negative regulation of NF-κB signaling in somatic cells as well as in ES cells might give more insights into therapeutics targeting NF-κB signaling.