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The activity of NF-kappaB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfkappab or ikappaB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-kappaB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-kappaB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-kappaB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NF-kappaB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-kappaB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-kappaB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-kappaB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow.