<p>The skin microbiome is composed of a diverse community of microorganisms, including bacteria, fungi, viruses and mites. These microorganisms have a crucial role in maintaining skin health, protecting against pathogens and modulating immune responses. In recent years, our understanding of the skin microbiome has expanded substantially with the deployment of metagenomic sequencing. This technology, by reconstructing microbial species, strains and gene pathways in the microbiomes of different cohorts, has led to identification of numerous therapeutic targets and thus propelled the development of therapeutic approaches that are aimed at leveraging these microorganisms to treat skin conditions and to improve skin health. In this Review, we discuss the composition, ecology, functions and therapeutic horizons of the human skin microbiome, presenting examples of studies that highlight potential therapeutic targets in the skin microbiome, ongoing progress in the development of skin microbiome-based therapeutics and challenges.</p>