The intestine harbors a large and diverse community of microorganisms, collectively known as the microbiota. The intestinal microbiota serves integral roles in multiple aspects of host development and physiology, including fortification of the host immune system and regulation of host nutrient metabolism. Perturbation of these commensal host-microbe relationships is thought to contribute to the etiology of human diseases, including inflammatory bowel disease and obesity. Despite the significant impact of the microbiota on host biology, the mechanisms underlying these host-microbe interactions remain largely unknown. In my laboratory, we use the zebrafish model system to address these important gaps in our knowledge. By comparing germ-free zebrafish to those colonized with a normal microbiota, we have identified host innate immune and nutrient metabolic responses to the microbiota that have been evolutionarily conserved between zebrafish and mammals. The optical transparency of the developing zebrafish, as well as the amenability of the zebrafish to genetic and chemical screens, provides new opportunities for investigating host-microbe interactions. We are pursuing molecular and genetic approaches in gnotobiotic zebrafish and selected members of the intestinal microbiota, to identify the microbial signals and host signal transduction mechanisms that mediate innate immune and nutrient metabolic responses. The characterization of factors that help establish and sustain these conserved host-microbe relationships in the digestive tract should lead to new ways of manipulating nutrient metabolism and immunity in humans and other vertebrates.