Powered by high-speed high-throughput next-generation genomic technologies, life science and biotechnology are being transformed. In our laboratory, we apply genomic and metagenomic tools to study model microbes and microbial communities. Multi-omics systems-level understanding of the Escherichia coli cell factory may open the door to synthetic biology and next-generation biotechnology. Analysis of genomes sampled from a long-term evolution experiment revealed that the coupling between genomic and adaptive evolution is complex and can be counterintuitive even in a constant environment. The microbiome, comprised of the microbiota and its collective genomes called the metagenome, is an integral part of our body and the ecosystem. Systems understanding of host physiology can be possible only if the microbial counterparts that reside in are fully appreciated and both are considered as a unit, i.e. holobiont. Recent analyses reveal that a myriad of microbial members, mutualistic, commensal, or pathogenic to the host, play pivotal roles in health and disease by producing diverse macromolecules and metabolites. Host-microbiota relationships in the plant rhizosphere and the human gastrointestinal tract, as well as the dynamics of microbial communities, will be presented as examples. In the talk, efforts to develop probiotics or more preferably pharmabiotics for the prevention or treatment of plant diseases or gastrointestinal cancers will also be presented. Synthetic biology concepts and toolkits enable us to modulate the microbiome to maintain (eubiosis) or regain (rebiosis) homeostasis, and even to transform it to become preventive or curative.