Recent research about the human microbiome has transformed our understanding of its role in human health while it is progressively recognized as a key factor in drug effectiveness and safety. Therefore, this chapter explores the role of microbiota biomarkers in biomarker-driven drug therapy and how they will shape the future of precision medicine and drug design. Understanding individuals as holobiont and knowledge about the complex multidirectional interaction between non-antibiotic drugs, gut microbiota, and host are critical to developing microbial biomarkers that enhance the drug’s outcomes and safety. Microbiota biomarker-driven drug therapy can help predict individual responses to specific drugs, personalize medicine dosage, guide microbiota-targeted interventions, and monitor the drug efficacy, in case of the personalized treatments. Progress in nanotechnology, high-throughput next-generation sequencing, machine learning, artificial intelligence, and building comprehensive microbiome databases are expected to enhance the predictability and applicability of this approach. While there are challenges to overcome, the ongoing advancements in technology provide a hopeful outlook for the future of microbiota biomarker-driven precision medicine that will make therapies more precise, effective, and patient-specific.