When a new scientific discipline is born, there is an initial natural history phase, where explorers map out the contours of the unknown. For the past couple of decades we have characterized the form and function of microbial ecosystems in and on the human body. Now, with this wealth of information collected on the human microbiome serving as a foundation, we have entered into a new phase of testing targeted, mechanistic hypotheses for how our microbiota contribute to the etiologies of diseases. ISB is hosting a series of events in October that highlight recent in silico, in vitro, and in vivo advances towards engineering the gut microbiome to resolve complex diseases.