There is rapid development in the generation of various human skin models. These encompass simple 2D models and more sophisticated 3D models [1,2] including immunocompetent skin models. [3] Human skin models offer one major advantage that should favour their future use: They are human! This simple statement may have important implications when investigating human skin-microbiota interactions. Many mouse models are in use to analyse skin physiology and biology, and it is beyond question that such mouse models help to address specific in vivo issues. However, mouse skin differs from human skin in many ways. In addition to differences in the anatomical structure (mouse skin is thinner due to fewer keratinocytes layers and contains more hair follicles), there are marked differences in gene expression. Gerber et al discovered that there is only 30% identity between the top human-and mouse skin-associated genes. The authors conclude that this huge diversity may explain why data generated in mouse models often fail to translate into humans. [4] There are also important differences in the composition of barrier-related structure proteins building the epidermal differentiation complex. [5] Moreover, human skin harbours different subsets of immune cells and produces different cytokines as compared to mouse skin. [6] Similarly, there are also distinct differences between skin-derived mouse and human antimicrobial peptides (AMPs), for example RNase 7 or SKALP (skin-derived antileukoprotease). This may have crucial consequences because AMPs are an important component of innate cutaneous defense, and there is increasing evidence that AMPs shape the microbiota and the microbiota in turn modulate AMP expression. [7,8] For example, RNase 7 is a major human skin-derived AMP playing an important role in human cutaneous innate defense by controlling the growth of various microbes.