The NF-κB transcription factor is a critical regulator of the immune system, and is responsive to a large number of stimuli. Different stimuli engage signaling pathways to activate NF-κB, and effect distinct cellular responses. Mathematical modeling of the NF-κB network has been useful in studying the dynamic and cross-talk regulation of NF-κB. In this review, we discuss the regulation of NF-κB activity in response to different types of stimuli, including inflammatory signals, developmental cues, metabolic stress, and DNA damage. The distinct molecular mechanisms engaged in each pathway for activating and terminating NF-κB activity are discussed. In addition, we summarize the evidence for cross-talk mechanisms that allow for different stimuli to be integrated within the NF-κB signaling module to produce synergistic or qualitatively different signaling outcomes.