The difficulties to find a conventional vaccine against Staphylococcus aureus and the increasing resistance of S. aureus to many antibiotics demand the exploration of novel therapeutic options, such as by targeting virulence determinants and using specific antibodies in an antitoxin-like approach. Community-associated methicillin-resistant S. aureus (CA-MRSA) strains have recently emerged predominantly in the US, causing epidemic outbreaks of mostly skin and soft tissue infections, but also more dramatic and sometimes fatal diseases. MRSA is now the most frequent cause of death by a single infectious agent in the US. The fact that, at least in the US, CA-MRSA infections are almost entirely due to one sequence type, USA300, gives researchers a novel, unique chance to focus on one clone in their efforts to analyze pathogenesis in a clinically important S. aureus. While the molecular underpinnings of the exceptional virulence and transmissibility of USA300 are not yet well understood, recent findings indicate that increased expression of widespread virulence determinants and acquisition of mobile genetic elements have to be considered. Delineating the relative importance of virulence determinants in USA300 and other important clinical strains is a key endeavor needed to develop a potential antitoxin for CA-MRSA disease.