This paper introduces a wireless electro- chemical sensing system for in vivo small-molecule sensing using reagent-less structure-switching aptamers. The system consists of a 65-nm CMOS electrochemical sensing circuit with an on-chip waveform generator, a Bluetooth microcontroller (MCU), and a battery, which allow for robust wireless recording in a freely moving animal. The device can perform data acquisition every 10 seconds, including wireless data transfer, and consumes an average current of 3mA after duty cycling. Multiple steps in the data processing for noise reduction are discussed. Real-time sensing of infused kanamycin concentration in the interstitial fluids (ISF) using “wire” electrodes is demonstrated on a freely moving rat with the device implanted under the skin. The paper also compares the results at different sensing locations and identifies the difference in their diffusion rates. Finally, the authors suggest that the technology can be adapted for monitoring other molecules using DNA aptamers of different sequences.