The skin and integumentary system allowed for terrestrial life to evolve. It did so in a world already dominated by a wide variety of microorganisms capable of inhabiting the outermost surfaces of our bodies. As so-called “next-generation sequencing” has influenced the past generation of scientific inquiry, so has our ability to observe the communities of microorganisms residing in association with their human hosts. Culture-independent and high-throughput sequencing technologies have provided the required tools to sequence a large portion of the DNA-bearing populations of life within a sample taken from a human body site of interest, thus giving us the required resolution to profile the composition of microbial communities. Shotgun metagenomic sequencing techniques can yield insight into the metabolic and functional capability of a microbial community. The specifics of how metagenomics and other technologies can be utilized for conducting research on the skin microbiome, as well as the required tools and recommended practices for analyzing microbial data, is described in the following section of this work. Moreover, the use of sequencing DNA barcodes in the bacterial 16S rRNA gene, a process sometimes referred to as metabarcoding, has allowed for the relatively quick and cheap analysis of skin microbial communities in studies of humans, animals, or the environment. However, there is still room for improvement of computational processing and algorithms used to accurately and precisely identify the bacteria from which the DNA encoding a region of the 16S rRNA gene was sequenced, thus increasing the accuracy of the overall research. We detail a program we developed that takes advantage of a Bayesian framework and the inherent structure of phylogenetic relationships between bacteria for determination of taxonomic identification in the third section. The remaining sections detail two studies of the skin microbiome, the former being an analysis of community temporal dynamics in an acute wound setting. Notably, this study reveals an association between the convergence of a wound’s microbiome with the microbiome of “healthy” adjacent skin and the speed at which that open fracture wound heals. The last section details an investigation of the cutaneous host response to the presence of microbiota. Specifically, we compared epidermis from germ-free mice to conventionally raised (colonized) mice in regard to gene expression (RNA-Seq), lipid composition, physiological attributes, and skin barrier function. Together, this work shows how computational processes can be used to better understand the host-microbe interactions in skin health and disease.