The human microbiome, consisting of trillions of microorganisms, plays a critical role in health and disease. Recent advances in DNA sequencing and omics technologies have significantly improved our understanding of the microbiome's structure and function in both healthy and diseased states. However, many challenges remain, including understanding the factors that influence microbiome composition and how variations in the microbiome affect health and disease. This review highlights the current state of knowledge linking the microbiome to human disease, focusing on human studies and highlighting mouse studies when human studies are not available. It discusses factors influencing the microbiome, including human genetics, immune interactions, diet, antibiotics, and lifestyle. The microbiome is highly dynamic, with changes in diet, lifestyle, and environmental exposure affecting its composition. The microbiome's stability and resilience are also important, with long-term studies showing that the microbiome remains relatively stable in adults. The microbiome's role in disease is increasingly recognized, with changes in the microbiome and its metabolome correlated with various illnesses, including inflammatory bowel disease, cancer, and major depressive disorder. The review also discusses the importance of mechanistic studies to move from correlation to causation and to develop novel clinical interventions. The potential for microbiome research to translate into clinical practice is significant, with the ability to identify biomarkers for disease and to develop personalized treatments. Future studies will focus on understanding the microbiome's role in health and disease, developing translational potential, and integrating microbiome research with clinical and epidemiological studies. The review emphasizes the need for continued research to fully understand the microbiome's impact on human health and to develop effective interventions.The human microbiome, consisting of trillions of microorganisms, plays a critical role in health and disease. Recent advances in DNA sequencing and omics technologies have significantly improved our understanding of the microbiome's structure and function in both healthy and diseased states. However, many challenges remain, including understanding the factors that influence microbiome composition and how variations in the microbiome affect health and disease. This review highlights the current state of knowledge linking the microbiome to human disease, focusing on human studies and highlighting mouse studies when human studies are not available. It discusses factors influencing the microbiome, including human genetics, immune interactions, diet, antibiotics, and lifestyle. The microbiome is highly dynamic, with changes in diet, lifestyle, and environmental exposure affecting its composition. The microbiome's stability and resilience are also important, with long-term studies showing that the microbiome remains relatively stable in adults. The microbiome's role in disease is increasingly recognized, with changes in the microbiome and its metabolome correlated with various illnesses, including inflammatory bowel disease, cancer, and major depressive disorder. The review also discusses the importance of mechanistic studies to move from correlation to causation and to develop novel clinical interventions. The potential for microbiome research to translate into clinical practice is significant, with the ability to identify biomarkers for disease and to develop personalized treatments. Future studies will focus on understanding the microbiome's role in health and disease, developing translational potential, and integrating microbiome research with clinical and epidemiological studies. The review emphasizes the need for continued research to fully understand the microbiome's impact on human health and to develop effective interventions.