Histophilus somni, besides being firstly isolated as the cause of thromboembolic meningoencephalitis, is nowadays regarded worldwide as one of the primary bacterial causes of bovine respiratory disease (BRD), as well as of some reproductive and cardiovascular diseases in both beef and dairy cows, leading to health impairment, economic losses, and higher need of antimicrobial treatments. Even if H. somni is usually find a commensal bacterium in the respiratory and reproductive tracts of cattle, some external conditions, such as stress related immunosuppression and previous action of other pathogens, can induce H. somni to become pathogenic. Even if there still is a lack in the knowledge about the precise mechanisms of its pathogenicity, several virulence factors have been identified that can explain its pathogenicity. The high variability in the genetic aspect of the antigens exposed on the bacterial surface, their ability to undergone to phase variation and to bind the antibodies, as well as its ability to form a biofilm, to acquire iron as a nutrient and to bind some of the host’s immunoglobulins (IgGs) through the expression of outer membrane proteins (OMPs) are some of the main virulence factors that can both trigger its pathogenicity and reduce the effectiveness of the immune defences and of some treatment options. Indeed, the treatment of symptomatic diseases caused by H. somni is difficult, due to both the high variability in the antigens expressed as well as due to the difficulty in intervening promptly at the onset of the first symptoms and in identifying affected animals early in the course of disease. In any case the efficacy of the treatment with antimicrobial is scant and vague, even if it has a good susceptibility toward many antimicrobials in vitro. The use of prevention strategies such as specific vaccinations against H. somni, and against the main pathogens related to BRD, such as M. haemolytica or Bovine Respiratory Syncytial Virus, common cofactors for H. somni, may be beneficial as an approach to control H. somni outbreaks. Indeed, even if the mechanisms of protective immunity against H. somni are still not so well understood, antibodies are likely to be an important part of the protection system, and vaccination is thus used as the primary way to counteract H. somni. However, the high genetic variability of the antigens, as well as their ability to undergo to phase variation, and the intrinsic differences between specific respiratory or urogenital strains, can reduce the efficacy of the vaccines. Some improvements in the efficacy of vaccines can be done by using innovative technologies such as reverse vaccinology, to be able to find a higher number of target genes that encode for more surface proteins, that are more likely to be potential antigenic vaccine candidates. The aim of the present work was to give an overview of the main clinical syndromes associated with H. somni, as well as on the current knowledges about epidemiology, transmissions ways, virulence determinants, host-immune response and treatment and prevention strategies.