<p>The ‘human metagenome’ comprises the collective genomes of the microorganisms living in or on the human body. Since about the mid-2010s, the application of culture-independent, high-throughput genetic sequencing technologies has driven the expansion of the human microbiome database and the exponential growth in metagenomics data; moreover, together with substantial advances in bioinformatics tools, it has fuelled increased recognition of the microbial variation in human health and disease. However, the functions microorganisms can perform are still largely unknown, and the potential of metagenomics data to reveal microbial functionality has not been fully unlocked. At the same time, advances in artificial intelligence in structural biology have revolutionized the prediction of protein structures and functions. In this Review, we present an overview of metagenomics data analysis, highlighting emerging opportunities and future directions. These investigations include 1D species identification and abundance profiling, 2D assessments of strain-level genetic variations, 3D analysis for protein structures and annotation, and 4D studies of spatial–temporal dynamics.</p>