Abundant data support a key role for the transcription factor nuclear factor-κB (NF-κB) signaling pathway in controlling the initiation and progression of human cancer. NF-κB and associated regulatory proteins such as IκB kinase (IKK) are activated downstream of many oncoproteins and there is much evidence for the activation of NF-κB-dependent target genes in a variety of solid tumors and hematologic malignancies. This review focuses on the mechanisms by which the NF-κB pathway is activated in cancer and on the oncogenic functions controlled by activated NF-κB. Additionally, the effects of NF-κB activation in tumors relative to cancer therapy are also discussed.