Staphylococcus aureus (S. aureus) infections are a major healthcare challenge and new treatment alternatives are needed. S. aureus septic arthritis, a debilitating joint disease, causes permanent joint dysfunction in almost 50% of the patients. S. aureus bacteremia is associated with higher mortalities than bacteremia caused by most other microbes and can develop to severe sepsis and death. The key to new therapies is understanding the interplay between bacterial virulence factors and host immune response, which decides the disease outcome. S. aureus produces numerous virulence factors that facilitate bacterial dissemination, invasion into joint cavity, and cause septic arthritis. Monocytes, activated by several components of S. aureus such as lipoproteins, are responsible for bone destructions. In S. aureus sepsis, cytokine storm induced by S. aureus components leads to the hyperinflammatory status, DIC, multiple organ failure, and later death.