Research into the microbiome—the indigenous microbial communities (microbiota) and the host environment that they inhabit—has changed clinicians’ ideas about microbes in human health and disease. Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes. Thus disease can result from a loss of beneficial functions or the introduction of maladaptive functions by invading microbes. This review will show how an understanding of the dynamics and function of the indigenous microbiota has altered our view of microbes in maintaining homeostasis and causing disease. It will discuss how disruption of the beneficial functions of the microbiota can lead to disease. Methods for studying the microbiota will be introduced as part of a conceptual framework for using these methods to delineate novel roles for microbes in health. Key associations between specific changes in the microbiome and disease will be discussed. This will lead to an explanation of how the intentional manipulation of the microbiota, either by restoring missing functions or eliminating harmful functions, may lead to novel methods to prevent or treat a variety of diseases. With the explosion of studies relating the microbiome to health and disease, this review aims to provide a foundation for clinicians to follow this developing area of biomedical research.