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A poorly appreciated truism is that the information contained within the mammalian genome is insufficient for full development of several organ systems, notably the gut, immune system, and other sensory organs. The required information is derived from the environment, including the microbial environment. This suggests that the microbiota is a source of regulatory signals, some of which may be suitable for exploitation for therapeutic purposes. Indeed, it could have been deduced from comparative studies of germ-free and conventionally colonized animals almost half a century ago that the gut microbiota influences the development and maturation of the digestive and immune systems. In some instances, the signals involved have recently been defined molecularly. This opens the possibility of a “bugs to drugs” program of discovery, in which the gut ecosystem is explored as a repository from which bioactives or novel drugs might be mined and translated to human health care. Specific examples of mining microbe–microbe interactions, host–microbe interactions, and host–microbe–dietary interactions have immediate clinical implications. The future of drug discovery in gastroenterology is likely to reside in the lumen!