Purpose <p>Regenerative engineering has evolved as an interdisciplinary field integrating biology, materials science, and clinical innovation, with transformative applications for tissue and organ regeneration. This review highlights key advancements, from foundational engineering of tissues and organs to cutting-edge trends such as cell and gene therapy, AI-driven design and modeling, molecular engineering, complex system bioprinting, while addressing challenges and future directions. This review also aims to honor Nicholas A. Peppas for his landmark contributions for the development of functional biomaterials, one of the cornerstones for regenerative engineering.</p> Method <p>This work synthesizes insights from the historical development of regenerative medicine and tissue engineering and recent achievements, focusing on developments in scaffold design, bioprinting, molecular tools like CRISPR and mRNA technologies, AI integration, and translational hurdles of regenerative and tissue engineering for clinical applications.</p> Results and Conclusion <p>This review explores key advancements in tissue engineering and regenerative medicine that are shaping the Future research direction And clinical applications. Foundational breakthroughs, such as decellularization techniques And 3D bioprinting, stem cell development, and novel biomaterials, have set the stage for transformative innovations. Recent progress includes AI-driven modeling, precise genome editing, cell-based gene/immunology therapy, scalable and complex organoid systems, and organ-on-chip systems, offering novel solutions to critical medical challenges. Despite these strides, challenges like ex vivo scalability, vascularization, and functional whole organ or multiple-organ systems remain key areas of focus required for further progress. The integration of cutting-edge tools—such as CRISPR, mRNA technologies, and AI-enabled automation and design—is accelerating the development of personalized and scalable tissue and organ regeneration for specific applications of clinical therapies.</p> Lay Summary <p>Regenerative engineering is an interdisciplinary field that combines biology, materials science, and clinical innovation to repair or replace damaged tissues and organs. Early breakthroughs—such as engineered skin, blood vessels, bone, liver, lung, and heart tissues—laid the foundation for more advanced biotechnologies, including stem cell therapies, 3D bioprinting, organ-on-chip, extracellular matrix (ECM) engineering, and bioscaffold design. These technologies aim to address pressing global challenges such as organ shortages and degenerative diseases by offering personalized and scalable solutions. For example, genome editing tools now enable precise corrections in patient-derived or stem cells, while emerging AI technologies are being developed to optimize cell differentiation, scaffold design, and tissue growth monitoring,&#xa0;enhancing both the availability and success rate of regenerative therapies. Although challenges remain—such as engineering complex organs&#xa0;and systems, ensuring safety and biocompatibility, and reducing costs—the field continues to progress rapidly, driven by emerging technologies that aim to deliver&#xa0;safe, accessible, and effective treatments for a broad range of patients.</p>