Haemophilus somnus (‘Histophilus somni’) is a Gram-negative bacterium and opportunistic pathogen associated with multisystemic diseases of bovines. Some strains of H. somnus are relatively avirulent, but are biochemically and antigenically similar to the virulent strains. Several virulence factors have been identified in H. somnus, of which lipo-oligosaccharide phase variation, induction of apoptosis, intraphagocytic survival and immunoglobulin Fc binding proteins have been well studied. The sequencing of the genomes of two strains of H. somnus has facilitated the identification of genes responsible for distinctive attributes within this species and related bacteria. The genetic characterization of this bacterium will enhance our understanding of H. somnus virulence factors and facilitate the development of new and improved vaccines. This review presents an overview of H. somnus virulence factors, their role in resistance to host defenses and pathogenesis, and the host immune response to this bacterium. Current areas of investigation in the post-genomic era and recent insights into new pathogenic mechanisms are also discussed.