Staphylococcus aureus is a highly successful bacterial pathogen owing to its abundance of cell surface and secreted virulence factors. It is estimated that 30% of the population is colonized with S. aureus, usually on mucosal surfaces, and methicillin-resistant S. aureus is a major public health concern. There have been multiple attempts to develop an S. aureus vaccine using one or more cell surface virulence factors as antigens; all of these vaccine trials have failed. In this Opinion article, we suggest that an over-reliance on rodent models and a focus on targeting cell surface components have been major contributing factors to this failure.