The human microbiome is emerging as a pivotal player in human health and disease, opening up new avenues for unveiling its roles and applications in disease in diagnosis and therapeutics. This chapter delves into the intricate world of human-colonized microorganisms, their diversity, commensalism versus pathogenesis, and translational values. In the realm of medical biotechnology, the rapid advancements in sequencing technologies have accelerated our understanding of the complex interplay between diverse microorganisms and the human body. This has led to the discovery of the unique microbial compositions across different body sites and their respective relations to organ-confined and/or systemic diseases. The chapter further explores the dynamic alterations in microbiomes in various diseases and the innovative therapeutic strategies leveraging these feature changes. The evolution in our understanding of the microbiome, akin to the rapid advancements in medical technology, is reshaping modern medical science. The exploration of the human microbiome thus stands at the forefront of medical biotechnology, making first-class health care unimaginable without it.