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Skin is our primary interface with the environment. A structurally and functionally complex organ that hosts a dynamic ecosystem of microbes, and synthesizes many compounds that affect our well-being and psychosocial interactions. It is a natural platform of signal exchange between internal organs, skin resident microbes, and the environment. These interactions have gained a great deal of attention due to the increased prevalence of atopic diseases, and the co-occurrence of multiple allergic diseases related to allergic sensitization in early life. Despite significant advances in experimentally characterizing the skin, its microbial ecology, and disease phenotypes, high-levels of variability in these characteristics even for the same clinical phenotype are observed. Addressing this variability and resolving the relevant biological processes requires a systems approach. This review presents some of our current understanding of the skin, skin-immune, skin-neuroendocrine, skin-microbiome interactions, and computer-based modeling approaches to simulate this ecosystem in the context of health and disease. The review highlights the need for a systems-based understanding of this sophisticated ecosystem. This article is categorized under: Infectious Diseases > Computational Models., (© 2020 Wiley Periodicals LLC.)