: The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two of these leukocidins, Leukocidin ED (LukED) and Hemolysin gamma AB (HlgAB), are necessary and sufficient to kill mice upon intravenous delivery in both infection and toxin challenge models. However, the mechanisms of lethality in these in vivo models are unknown. I will discuss our recent findings unraveling how LukED and HlgAB exhibit their lethal effect. Briefly, we discovered that these toxins cause vascular congestion and derangements in vascular fluid distribution that rapidly cause lethality. Surprisingly, the leukocidal and hemolytic functions of these toxins are dispensable for lethality. Instead, we identify the Duffy antigen receptor for chemokines (DARC) on nonhematopoietic cells as the critical target during lethal toxin challenge and bloodstream infection. We demonstrate that LukED and HlgAB target the vasculature and can directly injure primary human endothelial cells via DARC. Thus, endothelial cells are novel cellular targets for these leukocidins. The potential role of S. aureus leukocidins in manipulating the vascular dynamics of the host further highlights the importance of these virulence factors to S. aureus pathophysiology.