One Health is an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals, and environment ecosystems. All three domains are interconnected by microbiomes. Microbiomes are present universally and are connected by species exchange, impacting human and animal health but also environmental and biotechnological processes. Targeted control of the taxonomic and functional microbiome composition by microbial effectors such as antibiotics, antimicrobial peptides, and phages could be a game changer for these fields. However, the impact of microbial key factors on modulating microbiomes, the mechanisms implicated and the functional consequences, are barely understood. A novel approach which provides unique insights into the dynamics and the roles of microbial effectors is metaproteomics. The metaproteomics approach allows us to quantify the microbial composition and the expressed metabolic functions as well as to detect phages, antimicrobial resistance associated proteins, and non-ribosomal peptides. Leading European scientists of the Metaproteomics Initiative (https://metaproteomics.org/) formed a strategic alliance to set up a powerful and interdisciplinary network called METAMIC to capitalize on the potential of metaproteomics for developing novel strategies for microbiome control, manipulation/engineering, and restoration based on microbial effectors. METAMIC will achieve this by training a new generation of highly skilled microbiome and metaproteomics scientists, spreading their knowledge in research, industry, the medical sector, and public authorities. Developing novel metaproteomics workflows and exemplifying them in various clinical and biotechnological field studies will provides important steps towards better understanding and managing our microbiomes in the future, fitting the key EU missions, including “climate change”, “climate-neutral and smart cities”, “soil deal”, “restore ocean and water”, and “cancer”.