Large full-thickness skin defects still represent a significant clinical problem for burn, plastic, and reconstructive surgeons. In fact, high morbidity and mortality in the acute phase, as well as functionally and cosmetically devastating scarring represent vexing problems that are far from being solved in a satisfactory way. Although a variety of biologic dressings and cultured skin substitutes, in particular cultured epithelial autografts, have contributed to improve short- and long-term outcomes of patients in the past, the authors hypothesize that only the bioengineering of near-natural autologous full-thickness skin grafts harbors the potential for a dimensional breakthrough. This review gives an insight into the development and characteristics of the autologous full-thickness skin grafts available for clinical application to date. In addition, recent scientific progress toward the bioengineering of dermoepidermal skin grafts which comprise a functional vasculature, pigmentation, neural elements, and skin appendages is discussed.