Streptococcus pyogenes (Group A Streptococcus; GAS) causes millions of infections globally each year. Most infections remain local with mild symptoms, however, GAS can also disseminate systematically to cause life-threatening disease. The skin and the oropharynx are the primary reservoirs and entry sites of GAS in humans, but the immune defense mechanisms at these barrier sites represent a major knowledge gap. Langerhans cells (LCs) are key sentinel, antigen-presenting cells in the skin epidermis and oral mucosa that are distinguished by expression of the C-type lectin receptor langerin (CD207). In this study, we characterized the interactions between human LCs and GAS. Bulk RNA-sequencing of GAS-exposed primary human skin LCs showed induction of ccl3, ccl4, mmp12, and il10, suggesting that exposure triggers activation and migration of the LCs. In addition, we pinpointed langerin as one of the interacting LC receptors for a broad range, but not all, GAS emm types. Using a Krmit transposon mutant library in GAS M3 STAB902, we identified mga and emm as key GAS genes involved in langerin binding. Deletion of either gene in different M-type backgrounds significantly reduced langerin binding, which could be restored by plasmid complementation with emm3. Interestingly, langerin binding could not be transferred to Lactococcus lactis through heterologous expression of emm3, suggesting that additional GAS-specific factors are required to confer langerin binding. Overall, these results provide a better understanding of the immune mechanisms against GAS at main entry sites, which is important to prevent further bacterial dissemination and life-threatening disease.