Medication adherence monitoring has relied largely on indirect measures of pill ingestion including patient self-report, pharmacy refills, electronically triggered pill bottles, and pill counts. Our objective is to describe an ingestible biosensor system comprising a radio-frequency identification (RFID)-tagged gelatin capsule. Once the capsule dissolves in the stomach, the RFID tag activates to transmit a unique signal to a relay device which transmits a time-stamped message to a cloud-based server that functions as a direct measure of medication adherence. We describe a constellation of mobile technologies that provide real-time direct measures of medication adherence. Optimizing connectivity, relay design, and interactivity with users are important in obtaining maximal acceptability. Potential concerns including gut retention of metallic components of the ingestible biosensor and drug dissolution within a gelatin capsule should be considered. An ingestible biosensor incorporated into a medication management system has the potential to improve medication compliance with real-time monitoring of ingestion and prompt early behavioral intervention. Integration of ingestible biosensors for multiple disease states may provide toxicologists with salient data early in the care of poisoned patients in the future. Further research on device design and interventions to improve adherence is needed and will shape the evolving world of medication adherence.