The Rel/NF-κB transcription factors have emerged as novel therapeutic targets for a variety of human diseases and pathological conditions, including inflammation, autoimmune diseases, cancer, ischemic injury, osteoporosis, transplant rejection and neurodegeneration. Several US FDA-approved drugs may, in part, attribute their therapeutic effects to the inhibition of the Rel/NF-κB pathway. Strategies for blocking the Rel/NF-κB signaling pathway have inspired the pharmaceutical industry to develop inhibitors for I-κB kinase, however, this article focuses instead on identifying natural compounds that directly target and inhibit DNA binding and transcription activity of Rel/NF-κB. These include compounds containing a quinone core, an α,β unsaturated carbonyl and a benzene diamine. By investigating the mechanisms of action of existing natural inhibitors, novel strategies and synthetic approaches can be devised that will facilitate the development of novel and selective Rel/NF-κB inhibitors with better safety profiles.