Research on the gut microbiome, which first began to take shape with the advent of culture-independent, high-throughput sequencing, has now evolved into a highly active frontier in the life sciences. It is widely recognized that the gut microbiome is shaped by both host genetics and various environmental factors-including diet and lifestyle-and is closely associated with human physiology and a broad spectrum of diseases. Notably, environmental and lifestyle exposures appear to account for considerably more of the interindividual variation in gut microbiome composition than host genetics, which is precisely what makes the microbiome an attractive modifiable target. These advances have stimulated growing interest in translating gut microbiome research into the development of gut-microbiome-targeted foods and drugs to improve human health. However, such efforts remain challenging because of the complexity of microbiota–host interactions, substantial interindividual variability, and the disconnect between association studies, mechanistic understanding, and clinical efficacy. Against this background, this Special Issue brings together nine contributions that explore fundamental mechanisms, dietary modulation, microbiome heterogeneity, probiotic–drug interactions, and translational opportunities in the development of gut-microbiome-targeted foods and drugs.