As a member of bicomponent pore-forming leucocidins from Staphylococcus aureus (S. aureus), leukocidin ED (LukED) is encoded by two linked genes (lukE and lukD), which are co-transcribed into one mRNA. LukED is found to be able to target the chemokine receptor CCR5 to kill inflammatory macrophages, T cells, and dendritic cells, or to target receptor CXCR1/2 on neutrophils, monocytes and natural killer (NK) cells to enhance pathogenicity of S. aureus and death of the host. In addition, LukED can also lyse erythrocytes to release hemoglobin by binding to the Duffy antigen receptor for chemokines, and further promote the absorption of iron and growth of bacteria. The expression of LukED is regulated by the accessory gene regulatory-repressor of toxins (agr-rot) pathway and transcriptional regulators such as RpiRc and SpoVG. Studies show that lukED genes have a high frequency in S. aureus and have a close association with bloodstream infection, impetigo and antibiotic-associated diarrhea. Progress on researches of LukED not only improves our knowledge about clinical importance and the pathogenesis of S. aureus, but also provides insight into the development of potential novel anti-toxin drugs for the treatment of S. aureus infection.