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Signaling via NF-κB is a key process during inflammation and thus constitutes an attractive target for anti-inflammatory therapeutic interventions. Especially during initial hyperinflammatory states of an acute illness such as sepsis or in the course of chronic inflammation and autoimmune diseases inhibition of IKK-driven NF-κB activation provides a promising treatment strategy. Given its critical role in innate and adaptive immune responses, however, there is a certain amount of risk due to induced immunodeficiency that may follow inhibitory treatment. Moreover, its primary anti-apoptotic function suggests that blockade of NF-κB activation has dramatic effects on cell functions and survival and eventually worsens the course of an inflammatory disease.An overview of canonical and alternative NF-κB activation and its critical role in immune responses will be provided. A main topic focuses on recent animal studies and data derived from genetic studies in humans that provide an insight into potential effects of different therapeutic modulations of NF-κB inflammatory signaling. The pros and cons of NF-κB inhibition and treatment strategies will be critically reviewed.