Metagenomic analysis of the human microbiome has uncovered multiple links between our microbial complement and our health. However, several challenges remain on the road to completely unravel the diversity of the human microbiome and to exploit it within personalized medicine strategies. Such challenges include the characterization of the inter- and intra-personal variability of the human microbiome, of its extensive genetic diversity, and of its still hidden components. In my talk I will introduce such challenges and discuss how large-scale high-resolution integrative metagenomics can address them and have an impact on biomedical applications.