Numerous therapeutics demonstrate optimal absorption or activity at specific sites in the gastrointestinal (GI) tract. Yet, safe, effective pill retention within a desired region of the GI remains an elusive goal. We report a safe, effective method for localizing magnetic pills. To ensure safety and efficacy, we monitor and regulate attractive forces between a magnetic pill and an external magnet, while visualizing internal dose motion in real time using biplanar videofluoroscopy. Real-time monitoring yields direct visual confirmation of localization completely noninvasively, providing a platform for investigating the therapeutic benefits imparted by localized oral delivery of new and existing drugs. Additionally, we report the in vitro measurements and calculations that enabled prediction of successful magnetic localization in the rat small intestines for 12 h. The designed system for predicting and achieving successful magnetic localization can readily be applied to any area of the GI tract within any species, including humans. The described system represents a significant step forward in the ability to localize magnetic pills safely and effectively anywhere within the GI tract. What our magnetic pill localization strategy adds to the state of the art, if used as an oral drug delivery system, is the ability to monitor the force exerted by the pill on the tissue and to locate the magnetic pill within the test subject all in real time. This advance ensures both safety and efficacy of magnetic localization during the potential oral administration of any magnetic pill-based delivery system. magnetic pills | retention | localization | drug delivery F or many orally administered pharmaceuticals, increased residence time in a particular region of the gastrointestinal (GI) tract would greatly improve their therapeutic benefit (1-3). Typically, physiological digestive processes govern the GI residence of standard pills. We have developed a magnet-based delivery system visualized by biplanar videofluoroscopy in vivo that yields real-time monitoring and control over the duration of GI residence of model magnetic pills in the small intestines of rats both as a tool for investigating the GI site-specific absorption and action of therapeutics and as a critical step towards enabling clinical localization of magnetic pills. Our system can safely and reliably retain drugs for a user-defined duration in any region of the GI with the ability to monitor and control the force applied by the orally ingested magnet to the intestinal wall.