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The gastrointestinal (GI) tract offers the opportunity to detect physiological and pathophysiological signals from the human body. Ingestible electronics can gain close proximity to major organs through the GI tract and therefore can serve as clinical tools for diagnostics and therapy. In this Review, we summarize the physiological and anatomical characteristics of the GI tract, which present both challenges and opportunities for the development of ingestible devices. We describe recent breakthroughs in materials science, electrical engineering and data science that have permitted the exploration of technologies for sensing and therapy via the GI tract. Novel sensing opportunities include electrochemical, electromagnetic, optical and acoustic protocols, which have the capacity to sense luminal or extra-luminal analytes in the GI tract. We review therapeutic interventions, such as anatomical targeting for drug delivery …