Self-management of health and disease control using implantable biosensors is presently evolving strongly. Implantable biosensors require high selectivity and sensitivity, robust stability, temporal resolution, and device miniaturization. Electrochemical enzymatic biosensors that utilize specifically selective enzymes to convert the concentration of biomarker metabolites into electrochemical signals hold great promise to meet these criteria. As for electrochemical enzyme biosensors in continuous glucose monitoring, which have enjoyed great commercial success, amperometric biosensors have so far dominated enzymatic biosensor research and development. Potentiometric enzymatic biosensor research is, however, emerging with increasing strength, in particular due to greater promise for miniaturization. This minireview focuses on how to empower potentiometric enzymatic biosensors with high temporal resolution for continuous in situ monitoring of metabolites using the innovative non-equilibrium approach.