Recent genetic evidence has established a pathogenetic role for NF-κB signaling in cancer. NF-κB signaling is engaged transiently when normal B lymphocytes respond to antigens, but lymphomas derived from these cells accumulate genetic lesions that constitutively activate NF-κB signaling. Many genetic aberrations in lymphomas alter CARD11, MALT1, or BCL10, which constitute a signaling complex that is intermediate between the B-cell receptor and IκB kinase. The activated B-cell-like subtype of diffuse large B-cell lymphoma activates NF-κB by a variety of mechanisms including oncogenic mutations in CARD11 and a chronic active form of B-cell receptor signaling. Normal plasma cells activate NF-κB in response to ligands in the bone marrow microenvironment, but their malignant counterpart, multiple myeloma, sustains a variety of genetic hits that stabilize the kinase NIK, leading to constitutive activation of the classical and alternative NF-κB pathways. Various oncogenic abnormalities in epithelial cancers, including mutant K-ras, engage unconventional IκB kinases to activate NF-κB. Inhibition of constitutive NF-κB signaling in each of these cancer types induces apoptosis, providing a rationale for the development of NF-κB pathway inhibitors for the treatment of cancer.