The human gut harbors diverse microbes that play a fundamental role in the well-being of their host. The constituents of the microbiota—bacteria, viruses, and eukaryotes—have been shown to interact with one another and with the host immune system in ways that influence the development of disease. We review these interactions and suggest that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in our microbiota.