NF-kappa B transcription factors regulate the expression of a variety of genes involved in immune responses and cell growth. In higher vertebrates, the NF-kappa B family encompasses five distinct members. Three NF-kappa B proteins, p65/RelA, RelB, and c-rel/Rel, have high transactivating potential in addition to their DNA binding activity. Two subunits, NF-kappa B1p50 and NF-kappa B2p52, coded respectively by the NFKB1 and NFKB2 genes, may only have DNA binding activity. Moreover, p50 and p52 subunits are translated as precursors, respectively p105 and p100, which can be processed into the mature active forms by the removal of their carboxy-terminal ankyrin domain. The five proteins share a homologous amino-terminal domain (rel domain) involved in DNA binding, dimerization, nuclear transport, and binding of regulatory subunits. All members form homo- and heterodimeric complexes with different DNA binding specificity and transactivating potential. Structural alterations of some members of the NF-kappa B gene family have been observed in lymphoid malignancies. In particular, the NFKB2 gene, localized on chromosome 10q24, represents a candidate proto-oncogene, since it has been found rearranged in certain types of lymphoma and more commonly in cutaneous lymphoma. Molecular analysis indicated that these rearrangements may occur as a consequence of chromosomal translocations or small internal chromosomal deletions. Rearrangements cluster within the carboxy-terminal ankyrin domain of the NFKB2 gene leading to the production of carboxy-terminally truncated proteins which, in some cases, are fused to heterologous protein domains. Experimental data showed that these abnormal proteins are constitutively localized in the nucleus, have lost the transcriptional repressor functions typical of normal NF-kappa B2p52 and may be capable of transactivation activity. These findings suggest that abnormal NFKB2 proteins may contribute to lymphomagenesis by altering the NF-kappa B system, both quantitatively and qualitatively, and leading to the activation of specific subsets of kappa B-controlled genes.