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The Staphylococcus sp. are a dominant part of the human skin microbiome and present across the body. Staphylococcus epidermidis is a ubiquitous skin commensal, while S. aureus is thought to colonize at least 30% of the population. S. aureus are not only colonizers but a leading cause of skin and soft tissue infections and a critical healthcare concern. To understand how healthy human skin may differentiate commensal bacteria, such as S. epidermidis, from the potential pathogen methicillin-resistant S. aureus (MRSA), we use ex vivo human skin models that allow us to study this host-bacterial interaction in the most clinically relevant environment. Our work highlights the role of the outer stratum corneum as a protective physical barrier against invasion by colonizing Staphylococci. We show how the structural cells of the skin can internalize and respond to different Staphylococci with increasing sensitivity. In intact human skin, a discriminatory IL-1β response was identified, while disruption of the protective stratum corneum triggered an increased and more diverse immune response. We identified and localized tissue resident Langerhans cells (LCs) as a potential source of IL-1β and go on to show a dose-dependent response of MUTZ-LCs to S. aureus but not S. epidermidis. This suggests an important role of LCs in sensing and discriminating between bacteria in healthy human skin, particularly in intact skin and provides a detailed snapshot of how human skin differentiates between friend and potential foe. With the rise in antibiotic resistance, understanding the innate immune response of healthy skin may help us find ways to enhance or manipulate these natural defenses to prevent invasive infection. Author summary: How healthy human skin can differentiate between commensal bacteria that live harmoniously on our skin and those bacteria that have the potential to cause invasive infection, is of great interest. Here we use ex vivo human skin models to show how the outer layer of human skin resists bacterial invasion and that disruption of this layer leads to increased infection and inflammation. We show how colonization of both intact and disrupted skin by Staphylococcus aureus causes an increased IL-1β signaling compared to the commensal S. epidermidis. We show that tissue resident Langerhans cells are well positioned throughout the skin epidermis and that MUTZ-LCs can differentiate commensal from pathogen via IL-1β. This work identifies one of the subtle, yet effective, pathways by which human skin differentiates commensals and pathogens. Understanding these mechanisms could lead to potential new treatment and prevention targets, mechanisms by which we can enhance innate immunity. [ABSTRACT FROM AUTHOR]