All animals, from cnidarians to humans, are colonized with microbes, and the greatest diversity and magnitude of these host-associated microorganisms resides within the intestine. Referred to as the gut microbiome, membership can be as simple as one species of bacteria or can be composed of hundreds to thousands of different microbes across the domains of life. The relationship between the gut microbiome and host span from beneficial to detrimental; interactions may be context-dependent and occur across host physiology and organ systems. In this Primer, we focus on the mammalian host to discuss basic mechanisms by which the gut microbiome impacts the host and review mechanisms by which hosts and the environment shape the microbiome. We end by highlighting key concepts and discussing future directions for the field that will be critical for generating the next generation of knowledge of the gut microbiome.