Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or Apo2L is a ligand of the TNF family interacting with five different receptors of the TNF receptor superfamily, including two death receptors. It has attracted wide interest as a potential anticancer therapy because some recombinant soluble forms of TRAIL induce cell death predominantly in transformed cells. The nuclear factor-kappaB (NFkappaB)?Rel family of proteins are composed of a group of dimeric transcription factors that have an outstanding role in the regulation of inflammation and immunity. Control of transcription by NFkappaB proteins can be of relevance to the function of TRAIL in three ways. First, induction of antiapoptotic NFkappaB dependent genes critically determines cellular susceptibility toward apoptosis induction by TRAIL-R1, TRAIL-R2, and other death receptors. Each of the multiple of known NFkappaB inducers therefore has the potential to interfere with TRAIL-induced cell death. Second, TRAIL and some of its receptors are inducible by NFkappaB, disclosing the possibility of autoamplifying TRAIL signaling loops. Third, the TRAIL death receptors can activate the NFkappaB pathway. This chapter summarizes basic knowledge regarding the understanding of the NFkappaB pathway and focuses on its multiple roles in TRAIL signaling.