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Staphylococcus aureus, the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive infection in these settings remain unclear. Here we show that the host androgens testosterone and dihydrotestosterone promote S. aureus pathogenesis and skin infection. Without the secretion of these hormones, skin infection in vivo is limited. Testosterone activates S. aureus virulence in a concentration dependent manner through stimulation of the agr quorum sensing system, with the capacity to circumvent other inhibitory signals in the environment. Taken together, our work defines a previously uncharacterized inter-kingdom signal between the skin and the opportunistic pathogen S. aureus and identifies the mechanism of sex-dependent differences in S. aureus skin infection., One-Sentence Summary: Testosterone promotes S. aureus pathogenesis through activation of the agr quorum sensing system.