Included in the armamentarium of antimicrobial defenses of human skin are the RNases. In this issue, Abtin et al. report new details about how this antimicrobial system is deployed. Although present throughout the epidermis, RNases appear to be free to act only within the stratum corneum. Elsewhere in the epidermis RNases are complexed with an inhibitory protein. In the stratum corneum proteases degrade the inhibitor, freeing the RNase and liberating it to function in antimicrobial defense.