Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the sae sensor kinase SaeS recognizes specific host stimuli is unknown. This thesis describes topology and mutagenesis studies of the sensing domain of SaeS, including basal expression and inducer-dependent phenotypes. Meanwhile, investigation of the sae auxiliary protein SaeP has identified a novel DNA binding function for this surface expressed lipoprotein that may be involved in fine-tuning the activity of the sae system. Overall, these structure-function studies provide insight into the sae signal transduction mechanism and raise some new questions regarding the role the sae system plays in the larger regulatory network S. aureus uses to control expression of its secreted virulence factors.