The transcription factor nuclear factor kappa B (NF-κB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-κB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-κB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-κB-activatory kinase IκB kinase, of the proteaseome, or of the DNA binding of NF-κB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-κB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-κB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.