<p>Self-sustainable bioelectronic devices that incorporate physiological synchronization functions are attracting increasing research interest because they could provide the variable functions required by living cells and tissues. However, from the popular viewpoint, self-sustainable bioelectronic devices are presently regarded to provide unidirectional stimulation, similarly to traditional bioelectronic devices that prompt cells and tissues to passively respond to the electrical cues delivered to them. The active effect of self-sustainable bioelectronic devices, which allows cells and/or tissues to autonomously alter the delivered electrical stimulation on demand, has not been fully recognized. This Perspective article presents the insight that self-sustainable bioelectronics could act as a bidirectional ‘bridge’ linking the electrical modulation of a cell or tissue with its growth and development requirements, thereby establishing a fully autonomous, closed-loop regulatory system. The interaction processes arising in microscopic (cell–piezoelectric material) and macroscopic (organ–electromechanically coupled device) systems are discussed, and typical examples of self-sustainable bioelectronics are presented, highlighting the key challenges of signal fidelity and long-term device stability. Predictions of the future trajectory of self-sustainable bioelectronics, and design considerations for the next generation of intelligent bioelectronic devices, are also included.</p>