The pursuit of an effective staphylococcal vaccine has never been more critical, as community-associated MRSA has become the most common bacterial infection in the US. In this commentary, we will highlight new discoveries in the host response to colonization and infection with S. aureus, discuss potential antigens that might be used as vaccines, and make recommendations as to how the field can move forward towards discovering the "holy grail" of an effective staphylococcal vaccine.