Microbiome, the complex community of microorganisms residing in various ecosystems, is pivotal in influencing host health and disease. Metabolomics, the comprehensive study of metabolites within biological systems, has emerged as a powerful tool for elucidating the functional interactions between the microbiome and its host. This chapter traces the evolution of metabolomics approaches in microbiome analysis, from their initial applications to their current state-of-the-art methodologies. Early metabolomics studies focused on cataloging and linking metabolites to specific microbiome functions. With advancements in analytical technologies, such as mass spectrometry and nuclear magnetic resonance, coupled with sophisticated bioinformatics tools, metabolomics now provides deeper insights into the dynamic metabolic exchanges between host and microbiome. These insights have led to the identification of disease biomarkers, the discovery of novel therapeutic targets, and a better understanding of the microbiome’s role in health and disease. As we explore the journey from the inception of metabolomics in microbiome research to today’s cutting-edge approaches, this chapter highlights the challenges and opportunities in the field and emphasizes the potential for future discoveries in personalized medicine and microbiome-targeted therapies.