Diabetes is affecting more than 25.8 million people in the United States, causing huge burden on the health care system and economy. Insulin injection, which is the predominant treatment for diabetes, is incapable of replenishing the lost insulin-producing beta cell in patients. Restoring beta cell mass through replacement therapy such as islet transplantation or beta cell regeneration through in vitro and in vivo strategies has attracted particular attentions in the field due to its potential to cure diabetes. In the aspect of islet transplantation, gene therapy, stem cell therapy, and more biocompatible immunosuppressive drugs have been tested in various preclinical animal models to improve the longevity and function of human islets against the posttransplantation challenges. In the islet regeneration aspect, insulin-producing cells have been generated through in vitro transdifferentiation of stem cells and other types of cells and demonstrated to be capable of glycemic control. Moreover, several biomarkers including cell-surface receptors, soluble factors, and transcriptional factors have been identified or rediscovered in mediating the process of beta cell proliferation in rodents. This review summarizes the current progress and hurdles in the preclinical efforts in resurrecting beta cells. It may provide some useful insights into the future drug discovery for antidiabetic purposes.