The two main forms of human diabetes mellitus (DM) are characterized by an absolute (type 1) and a relative (type 2) reduction in functional insulin-producing beta cell mass in the pancreas. Type 1 DM results from autoimmune assault of beta cells, and type 2 from the failure of pancreatic beta cells to sufficiently compensate for insulin resistance. Studies indicate that the incidence of both types is increasing rapidly to levels that constitute a global epidemic. Researchers are experimentally developing several conceptual approaches for increasing pancreatic beta cell mass and testing them for feasibility in treating the disease. The main sources for derivation of insulin-producing cells are embryonic and induced pluripotent stem cells, endogenous progenitor cells (both within and outside the pancreas), stimulation of beta cell proliferation, and genetic "reprogramming" of cells. Strategies to effectively address immune- and inflammation-mediated assault on existing and newly formed beta cells need to be refined. This review provides a description of beta cell ablation methods and a discussion of various types of studies of regenerative approaches-beta cell proliferation, islet cell transplantation, transdifferentiation, and the use of embryonic and induced pluripotent stem cells-to the treatment of diabetes mellitus. Although there has been much progress in this area, further research is needed to enhance understanding and improve therapeutic strategies for this widespread disease.