From digestion to pathogen resistance and immune system development, the gut microbiota and its collection of microbial genes are redefining what it means to be human. Despite tremendous advances in this field, there is still a limited understanding of how microbial metabolism in the gut impacts human health, which precludes the development of microbiota-targeted therapies. In this article, we discuss the increasing evidence emphasizing the importance of bacterial metabolism in the gut and discuss its intricate links with diet and pharmaceutical compounds leading to altered therapeutic outcomes. We also detail how applying and testing microbial ecology hypotheses will be crucial to fully understand the therapeutic potential of this host-associated community. Going forward, functional and mechanistic studies combining biomedical research, ecology, bioinformatics, statistical modeling, and engineering will be key in our pursuit of personalized medicine.