The lymphotoxin-β receptor (LTβR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-κB. In addition to activation of the classical NF-κB, ligation of this receptor induces the processing of the cytosolic NF-κB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-κB2 requires NIK and IKKα, while NEMO/IKKγ is dispensable for p100 processing. IKKβ-dependent activation of canonical NF-κB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1β, and MIP-2 in response to LTβR ligation. In contrast, IKKα controls the induction by LTβR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.