Next-generation sequencing and bioinformatics paved the way in deciphering the human gut microbiome and challenged fundamental postulates on the causal role of the microbiota for health and pathogenesis of infectious and noncommunicable diseases. To exploit the clinical relevance and potential of microbiome diagnostics and therapy, deep metagenomic sequencing with standardized, validated laboratory procedures, aiming at deciphering the microbiome at strain level and applying index-scores to allow classification of individual microbiomes as dysbiotic (associated with disease) or eubiotic (associated with health) should be implemented. By this means, metagenomically informed therapies with live biotherapeutic products, fecal microbiota transfer, pro-, pre-, or postbiotics might become a standard in personalized prevention and treatment of infectious and non-communicable diseases.