Regenerative medicine offers therapeutic approaches to treating non-regenerative diseases such as spinal cord injury and heart disease. Owing to the limited donor tissue available, cell-based therapy using cultured cells with supporting scaffolds has been proposed to rebuild damaged tissue. Early attempts at repairing skin and cartilage achieved significant success thanks to the simplicity of the tissue architecture, which later fueled enthusiasm for applying the same strategy to other types of tissue. However, more complex tissue functions require a more extensive vasculature and heterogeneous cell arrangements, which together constitute a significant hurdle in practical applications. Accordingly, recent years an increased interest has been in the use of decellularized matrices that retain the natural microarchitecture as the scaffold. However, although a number of engineering approaches have been suggested, self-organizing behavior such as cell proliferation, migration, and differentiation may still disorganize and frustrate the artificial attempts. This mini-review first provides examples of the early history of tissue engineering using skin and cartilage as examples, and then elaborates on the key technologies used to fabricate synthetic acellular scaffolds and cell/scaffold constructs with more complicated architectures. It also summarizes the progress achieved in the use of decellularized matrices for cell seeding as well as the recent success seen in self-organizing two- and three-dimensional tissue formation with the aid of biomathematical modeling. The review concludes by proposing the future integration of biomathematics, developmental biology, and engineering in concert with the self-organization approach to tissue regeneration.