Paramount to Staphylococcus aureus pathogenesis is the production of an array of pore-forming toxins (PFT). Among the PFT, S. aureus strains can produce up to five different bi-component leukocidins. Leukocidins were previously considered to be redundant toxins, but that notion has recently changed upon the identification of their specific cellular receptors. Among the bi-component leukocidins, LukAB is the newest and most divergent member of this subfamily of PFT. Interestingly, LukAB exhibits species-specificity preferentially targeting and killing human phagocytes, a tropism mediated by the selective targeting of the human CD11b receptor. While we have made significant progress in the past few years on how this toxin interacts with host cells, our understanding on the cellular pathways involved in LukAB-mediated cell death is very limited. In this seminar I will present our recent studies aimed at identifying the cellular pathways exploited by LukAB to kill human leukocytes. Our work has discovered that S. aureus uses LukAB to manipulate leukocytes in a manner dependent on the membrane site of contact. These novel observations are providing insight into how S. aureus evades the immune response, information critical for our ability to develop novel treatments to combat infections with this important pathogen.