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Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide, responsible for more than half a million deaths annually. CRC is a multistep process that entails the accumulation of genetic/epigenetic aberrations, which lead to the simultaneous failure of protective mechanisms and the activation of tumorigenic pathways. In most cases of CRC a deregulation of the Wnt-signaling pathway is required. The transcription factor nuclear factor κB (NF-κB) has been recognized as a key player in the initiation and propagation of CRC. Under physiological conditions, NF-κB orchestrates the inflammatory process and participates in the modulation of various steps of cell cycle and survival. It is normally kept in an inactive state in the cytoplasm by binding to a group of inhibitory proteins. Upon receipt of a signal, its inhibitor is phosphorylated and proteolytically degraded and NF-κB is actively translocated to the nucleus, where it facilitates target-gene transcription. Recent experimental data reveal the important role of NF-κB in tumor cells as well as in the surrounding "cancerous" and reactive microenvironment. Various tumor cell-derived and contextual cues feed constantly this vicious circuitry sustaining inflammation and promoting proliferation, angiogenesis, invasion and eventually metastasis. Therefore NF-κB along with its upstream and downstream network presents a rational target for therapeutic interventions. Numerous small molecules, inhibitory peptides, antisense RNAs, natural compounds, as well as gene therapy strategies interfere with multiple steps of the NF-κΒ signaling cascade. The design of NF-κΒ-targeted treatment may aid the efforts towards the pursuit of more efficient therapeutic measures devoid of severe systemic side-effects.