This volume reviews the current understanding of the taxonomy, disease syndromes, genetics, biology, and pathogenic factors of Histophilus somni, as well as the host immune response to this pathogen. H. somni is one of the most important bacterial pathogens in cattle and other ruminants, and its virulence factors are highly conserved with Haemophilus influenzae and other members of the Pasteurellaceae. H. somni has been recognized as a major cause of thrombotic meningoencephalitis, respiratory disease syndromes, myocarditis, reproductive disease syndromes, polyarthritis, mastitis, ocular disease, and septicemia. The only known habitats of H. somni are the mucosal surfaces of ruminants, making this bacterium an opportunistic pathogen. Although it is capable of causing inflammation at systemic sites and is toxic to epithelial and phagocytic cells, the bacterium wide array of virulence factors act primarily as a defense against, or to escape recognition from, host innate and adaptive immunity.