To this day, tissue reconstruction and replacement to address extensive tissue defects due to trauma, tumor resection, genetic and/or chronic diseases, or excessive debridement present a major clinical challenge. Traditional reconstructive techniques most commonly utilize autologous tissue. Undoubtedly, autologous composite tissue transfers or ‘‘flaps,’’ skin grafts, as well as the harvesting of bone and/or cartilage have substantially improved the health, functional, and aesthetic outcomes of millions of patients. Unfortunately, these procedures are not without their drawbacks. These include increased operative time, complexity, cost, limited availability of qualitative autologous tissue, wound healing complications, tissue flap failure, and substantial donor-site morbidity. Recently, collaborative research teams—consisting of surgeons, scientists, and engineers—have made substantial progress in their attempts to solve these problems. This article provides historical perspective, covers the major limitations of current standards of care, and reviews recent advances and future prospects in applied bioengineering in the context of tissue reconstruction, replacement, and regeneration.