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The transcription factor NF-κB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-κB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-κB family members play important roles. In this review, we provide an overview of established NF-κB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-κB transcriptional activity.