Technical Abstract: The red flour beetle Tribolium castaneum has contributed a wealth of knowledge on insect development but limited information about innate immunity. With its complete nucleotide sequence determined, we have taken the opportunity to annotate immunity-related genes and compare them with homologous molecules from other insects. In most cases, paralog counts are lower than those of Drosophila melanogaster or Anopheles gambiae but are substantially higher than Apis mellifera. We have identified around 300 candidate defense proteins based on sequence similarity to homologs known to participate in various immune responses. The genome contains probable orthologs for nearly all members of the Toll, IMD and JAK/STAT pathways. While the total numbers of clip-domain serine proteinases are approximately equal in the fly (37), mosquito (41) and beetle (48), linage-specific expansion of the family is discovered in all three species. Remarkably, multiple rounds of gene duplication have resulted in a cluster of 16 serpin genes in a small region of 50 kb! Among the 9 Toll-like proteins, four are located on the same clade with Drosophila Toll. The presence of scavenger receptors and other related proteins indicates a role of cellular responses in the entire system. The structures of some antimicrobial peptides drastically differ from those in other orders of insects. In summary, we have established a framework of information on Tribolium immunity, which may serve as a stepping stone for future genetic analyses of defense responses in a nondrosophiline model insect.