The health and fitness of animals, including humans, are influenced by the presence and composition of resident microbial communities. The development of rational microbial therapies to alleviate chronic immunological, metabolic and neurobiological diseases requires an understanding of the processes underlying microbial community assembly and the mechanisms by which microorganisms influence host traits. For fundamental discovery, simple animal models (that is, lower vertebrate and invertebrate species with low diversity microbiomes) are more cost-effective and time-efficient than mammal models, especially for complex experimental designs and sophisticated genetic screens. Recent research on these simple models demonstrates how microbiome composition is shaped by the interplay between host controls, mediated largely via immune effectors, inter-microorganism competition, and neutral processes of passive dispersal and ecological drift. Parallel research on microbiome-dependent host traits has identified how specific metabolites and proteins released from microorganisms can shape host immune responsiveness, ameliorate metabolic dysfunction and influence behavioural traits. In this Review, the opportunity for microbiome research on the traditional biomedical models zebrafish, Drosophila melanogaster and Caenorhabditis elegans, which command superb research resources and tools, is discussed. Other systems, for example, hydra, squid and the honeybee, are valuable alternative models to address specific questions.