Since the onset of the community-associated MRSA epidemic, a family of toxins produced by S. aureus, the leukocidins, have gained increasing attention as important virulence determinants and potential targets of intervention against this pathogen. The leukocidins known to be produced by clinical isolates of S. aureus include Panton-Valentine leukocidin (PVL), LukAB (also known as LukGH), LukED, and the γ-hemolysins HlgAB and HlgCB . Each of these two-component toxins is secreted as a pair of monomers that oligomerize to form a pore on the surface of phagocytes, lymphocytes, and natural killer cells, and they are important mediators of staphylococcal evasion of innate host defenses. The neutrophil represents the primary innate defense against S. aureus infection in humans, as evidenced in part by the clear predilection toward invasive S. aureus disease in patients with neutrophil defects . The leukocidins exert their effect at the level of the neutrophil and other phagocytes, binding receptors in the chemokine and complement receptor families [5–8], forming a pore, and potently lysing these cells, thereby facilitating infection in a variety of in vivo models [9–13]. S. aureus elaborates a number of additional pore-forming toxins outside the leukocidin family, prominently including alpha-hemolysin (Hla), which primarily targets erythrocytes, epithelial and endothelial cells, and lymphocytes. While the role of Hla has been carefully elucidated in numerous animal models , most of the leukocidins exhibit a markedly increased tropism for human leukocytes in comparison to murine cells , likely resulting in a previous underappreciation of the importance of the leukocidins when extrapolating from murine data.