Type I diabetes results from the autoimmune destruction of the insulin-secreting pancreatic β-cells, affecting many millions of people worldwide. The optimal treatment is to restore the endogenous supply of insulin either through the transplantation of pancreas or the transplantation of islets of langerhans or simply the β-cells. However, the donated pancreas organs are limited and the available organs are only able to treat a small portion of the diabetes patients. Thus, glucose-responsive, insulin-producing cells from human origin are urgently needed. The aim of this chapter is to give some insight views to how to turn the potential human pancreatic non-endocrine cells into cells that are capable of secreting insulin in response to glucose and ameliorating insulin-deficient diabetes conditions after transplantation.