NF-κB was first described as a B-cell-specific transcription factor that binds the κB site in the Ig κ light chain enhancer. Soon after, NF-κB activity was found to be inducible in all cell types and it is now known that members of the NF-κB/Rel family regulate many genes involved in immune and inflammatory responses. Until recently, only a single NF-κB signaling pathway was known, whereby NF-κB activity is stimulated by proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), as well as by pathogen-associated molecular patterns (PAMPs). However, two years ago, a second pathway leading to NF-κB activation was discovered. This pathway, now known as the alternative pathway, is activated by certain members of the TNF cytokine family but not by TNF-α itself. Recent results strongly suggest that the classical and alternative pathways to NF-κB activation have distinct regulatory functions, one that is mostly involved in innate immunity and the other in adaptive immunity.