The interest in studying the human skin microbiota emerged in the early twentieth century, and our knowledge on the composition and role of the skin microbiota has been growing along with the evolution of research methodologies. Traditionally, microbial samples were cultivated in various culture media, enabling the preferential growth of certain species, while hindering the identification of non-culturable microbes. During recent decades, culture-free analysis methods made possible the discovery of an astonishing taxonomic diversity of microbial life in nearly all habitats of Earth, including the human skin. This breakthrough was in large part due to the advent of molecular taxonomy, the identification of microbial species based not on phenotypical traits, but their genomic DNA content. This technological shift enables the identification of both culturable and non-culturable microbes, and at the same time opens up possibilities to discover novel species, revise taxonomic classification, and study the gene content of complete microbial communities, collectively referred to as the study of metagenomics. Importantly, in addition to qualitative information, metagenomics also provides the relative quantity of different taxa in a given sample and facilitates quantitative comparisons across a wide variety of conditions. In the present chapter, we are going to examine in detail the sampling methods, laboratory techniques and computational analyses required to characterize the human skin microbiome using metagenomic approaches.