Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains are causing a severe pandemic of mainly skin and soft tissue and occasionally fatal infections. The basis of their success is the combination of methicillin resistance at low fitness cost and high virulence. Investigation of the virulence potential of CA-MRSA, a key prerequisite for the development of anti-CA-MRSA therapeutics, has focused on strain USA300, which is responsible for the most serious CA-MRSA epidemic seen in the United States. Current data indicate that in this strain virulence evolved via increased expression of core-genome-encoded virulence determinants, such as alpha-toxin and phenol-soluble modulins, and acquisition of the phage-encoded Panton-Valentine leukocidin (PVL) genes. All these toxins impact disease progression in animal models of USA300 infection. In contrast, the basis of virulence in other CA-MRSA epidemics, which also include PVL-negative strains, is poorly understood.