Biosensors are of great interest for their ability to monitor clinically important analytes such as blood gases, electrolytes, and metabolites. A classic example is to monitor the dynamics of blood-glucose levels for treating diabetes. However, the current practice, based on a three decade old technology, requires a drop of blood on a test strip, which is in dire need of replacement. The increasing demands and interests in developing implantable glucose sensors for treating diabetes has led to notable progress in this area, and various electrochemical sensors have been developed for intravascular and subcutaneous applications. However, implantations are plagued by biofouling, tissue destruction and infection around the implanted sensors and the response signals must be interpreted in terms of blood or plasma concentrations for clinical utility, rather than tissue fluid levels. This review focuses on the potentials and pitfalls of implantable electrochemical sensors and presents our opinions about future possibilities of such implantable devices with respect to biocompatibility issues, long-term calibration, and other aging effects on the sensors.