Methicillin-resistant Staphylococcus aureus (MRSA) displays a remarkable array of resistance and virulence factors, which have contributed to its prominent role in infections of the critically ill. We are beginning to understand the function and regulation of some of these factors and efforts are ongoing to better characterize the complex interplay between the microorganism and host response. It is important that clinicians recognize the changing resistance patterns and epidemiology of Staphylococcus spp., as these factors may impact patient outcomes. Community-associated MRSA clones have emerged as an increasingly important subset of Staphyloccocus aureus and MRSA can no longer be considered as solely a nosocomial pathogen. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and appropriate, as delays in treatment are associated with adverse outcomes. Although vancomycin has long been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent have opened the door for existing and investigational agents demonstrating efficacy in this role.