Over the past 30 years, the scientific literature has been rife with articles that have chronicled the enduring threat and changing nature of Staphylococcus aureus as a leading cause of infectious morbidity and mortality to humans (Sheagren, 1984; Archer, 1998; Lowy, 1998; Otto, 2010). The most current surveys indicate that S. aureus is responsible for almost 500,000 hospitalizations and 30,000 deaths annually in the USA (Klein et al., 2007). At the turn of the twentieth century, the major threat was hospital-associated strains of methicillin resistant S. aureus (HA-MRSA) that are resistant to multiple antibiotics, and reports that some had acquired high level vancomycin resistance (Pearson, 2002; Weigel et al., 2003) seemed to assure the inevitable proliferation of strains that are resistant to all antibiotics. Although this crisis has not yet materialized, we have instead experienced the sudden emergence and global dissemination of hyper-virulent strains of community acquired MRSA (CA-MRSA). Another unexpected threat was the emergence of CA-MRSA in animal adapted strains of S. aureus, and their zoonotic transmission to humans. Conversely, some livestock-associated strains have undergone a recent evolutionary transition from human to animal hosts. Amidst this backdrop of newly emergent strains, common clonal types of HA-MRSA and methicillin susceptible S. aureus (MSSA) persist in their threat to health care, and attempts to lessen the impact through vaccine development have thus far been unsuccessful. In this Special Topics issue, recent advances in Staphylococcal research are captured in a collection of research, review, opinion, and methods articles, which we have assigned to the general themes of vaccine development, virulence, and immune evasion, metabolic activity in response to host environment, methods development, and comparative genomics and genome evolution.