Staphylococcus aureus, a Gram-positive bacterium, is a leading cause of human infection capable of invading most tissues of the human body. The superficial skin is a major infection site for S. aureus, which normally resides in 10-20% of healthy individuals. S. aureus produces virulence factors to transform from a skin commensal to a pathogen. However, it remains unclear how the host senses virulent but not commensal S. aureus to trigger skin inflammation. Using a model of epicutaneous S. aureus infection in which virulence genes are induced upon epidermal colonization, we have identified S. aureus virulence factors that are critical for the detection of the virulent pathogen and the induction of skin inflammation. Furthermore, we have identified host molecules in keratinocytes and signaling pathways that are essential for triggering skin inflammation in response to virulent S. aureus.