Piezoelectric materials, capable of converting mechanical stimuli into electrical signals, have emerged as promising tools in regenerative medicine due to their potential to stimulate tissue repair. Despite a surge in research on piezoelectric biomaterials, systematic insights to direct their translational optimization remain limited. This review addresses the current landscape by bridging fundamental principles with clinical potential. The biomimetic basis of piezoelectricity, key molecular pathways involved in the synergy between mechanical and electrical stimulation for enhanced tissue regeneration, and critical considerations for material optimization, structural design, and biosafety is discussed. More importantly, the current status and translational quagmire of mechanisms and applications in recent years are explored. A mechanism-driven strategy is proposed for the therapeutic application of piezoelectric biomaterials for tissue repair and identify future directions for accelerated clinical applications.