Biochemical coupling of transcription factor NF-κB to antigen and co-stimulatory receptors is required for the temporal control of T-cell proliferation. In contrast to its transitory activation during normal growth-signal transduction, NF-κB is constitutively deployed in T-cells transformed by the type 1 human T-cell leukemia virus (HTLV-1). This viral/host interaction is mediated by the HTLV-1-encoded Tax protein, which has potent oncogenic properties. As reviewed here, Tax activates NF-κB primarily via a pathway leading to the chronic phosphorylation and degradation of IκBα, a cytoplasmic inhibitor of NF-κB. To access this pathway, Tax associates stably with a cytokine-inducible IκB kinase (IKK), which contains both catalytic (IKKα and IKKβ) and noncatalytic (IKKγ) subunits. Unlike their transiently induced counterparts in cytokine-treated cells, Tax-associated forms of IKKα and IKKβ are persistently activated in HTLV-1-infected T cells. Acquisition of the deregulated IKK phenotype is contingent on the presence of IKKγ, which functions as a molecular adaptor in the assembly of pathologic Tax/IκB kinase complexes. These findings highlight a key mechanistic role for IKK in the Tax/NF-κB signaling axis and define new intracellular targets for the therapeutic control of HTLV-1-associated disease.