Summary: The vast majority of research on nuclear factor κB (NF-κB) signaling in the past 25 years has focused on its roles in normal and disease-related processes in vertebrates, especially mice and humans. Recent genome and transcriptome sequencing efforts have shown that homologs of NF-κB transcription factors, inhibitor of NF-κB (IκB) proteins, and IκB kinases are present in a variety of invertebrates, including several in phyla simpler than Arthropoda, the phylum containing insects such Drosophila. Moreover, many invertebrates also contain genes encoding homologs of upstream signaling proteins in the Toll-like receptor signaling pathway, which is well-known for its downstream activation of NF-κB for innate immunity. This review describes what we now know or can infer and speculate about the evolution of the core elements of NF-κB signaling as well as the biological processes controlled by NF-κB in invertebrates. Further research on NF-κB in invertebrates is likely to uncover information about the evolutionary origins of this key human signaling pathway and may have relevance to our management of the responses of ecologically and economically important organisms to environmental and adaptive pressures.