The Rel/NF-kappa B family is a group of structurally-related, tightly-regulated transcription factors that control the expression of a multitude of genes involved in key cellular and organismal processes. The Rel/NF-kappa B signal transduction pathway is misregulated in a variety of human cancers, especially ones of lymphoid cell origin, due either to genetic changes (such as chromosomal rearrangements, amplifications, and mutations) or to chronic activation of the pathway by epigenetic mechanisms. Constitutive activation of the Rel/NF-kappa B pathway can contribute to the oncogenic state in several ways, for example, by driving proliferation, by enhancing cell survival, or by promoting angiogenesis or metastasis. In many cases, inhibition of Rel/NF-kappa B activity reverses all or part of the malignant state. Thus, the Rel/NF-kappa B pathway has received much attention as a focal point for clinical intervention.