Understanding cross-species jump of bacterial pathogens – in this case Staphylococcus aureus – is a nagging question that has precedents in human and poultry and human and pigs. We recently described a human-bovine host jump of S. aureus CC8, a lineage that contains the notoriously virulent methicillin-resistant S. aureus (MRSA) USA300. Here we propose to study in depth the genomic and mechanistic correlates underlying this jump. The opportunity is unique for at least two reasons. First, it occurred rather recently and therefore the microbial genomes are not biased by prolonged divergent evolution. Second, the genetic differences between bovine and human isolates are still relatively circumscribed. They implicate two main Mobile Genetic Elements (MGEs), i.e. (i) the gain of a new MGE carrying a new surface protein that might promote S. aureus establishment in cows, and (ii) the loss of prophage phiSA3, which is important for S. aureus colonization of humans. Understanding the CC8 human-bovine jump is very attractive from both the veterinary and human medicine points of view. Indeed, bovine S. aureus CC8 appeared more aggressive than typical bovine S. aureus in herds. Thus, the detection of CC8 clones in mastitis should warn veterinarians for scrutiny. Moreover, the new MGE of bovine CC8 isolates may convey important antibiotic-resistance determinants (e.g. methicillin-resistance) back into humans. Thus, studying the CC8 human-to-bovine host jump does not only represent an academic opportunity to understand biology, but also to learn more on veterinary and human epidemiology in order to prevent the spread of infectious diseases and antibiotic-resistance.