To date, in the investigation of the role of S. aureus in WG, we face a paradoxical situation. On the one hand, clinical results obtained from treatment of WG patients with co-trimoxazole and studies assessing the impact of S. aureus on disease relapses strongly suggest that this bacterium contributes to disease pathophysiology. On the other hand, laboratory investigation of the possible mechanisms by which S. aureus is involved in WG is scarce, despite the fact that knowledge and tools to study this microorganism are abundant. In the present review, we discuss recent works investigating the possible pathophysiologic contribution of S. aureus to WG. Moreover, we propose a number of possibly relevant pathways of interaction of this bacterium with lymphoid and nonlymphoid cells of the WG host.