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