The recent emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) marked a quantum change in the biology and epidemiology of a major human pathogen. Various virulence determinants unique to CA-MRSA have been uncovered recently, which shed light on how these strains spread easily and sustainably among humans and frequently cause severe disease. The role of the Panton Valentine leukocidin (PVL) in CA-MRSA pathogenesis is a matter of much debate. Although epidemiological data have indicated a role for PVL in the CA-MRSA disease process, recent data from relevant animal models indicate that PVL does not impact virulence of prevalent CA-MRSA strains. Identifying specialized pathogenic traits of CA-MRSA remains a challenge that will yield new diagnostic tools and therapeutic targets for drug and vaccine development. Here, we discuss the roles of PVL, the arginine catabolic mobile element and phenol-soluble modulins in the pathogenesis of prevalent CA-MRSA strains.