SummaryInsulin-secreting pancreatic β-cells are essential regulators of mammalian metabolism. The absence of functional β-cells leads to hyperglycemia and diabetes, making patients dependent on exogenously supplied insulin. Recent insights into β-cell development, combined with the discovery of pluripotent stem cells, have led to an unprecedented opportunity to generate new β-cells for transplantation therapy and drug screening. Progress has also been made in converting terminally differentiated cell types into β-cells using transcriptional regulators identified as key players in normal development, and in identifying conditions that induce β-cell replication in vivo and in vitro. Here, we summarize what is currently known about how these strategies could be utilized to generate new β-cells and highlight how further study into the mechanisms governing later stages of differentiation and the acquisition of functional capabilities could inform this effort. Key words: β cell, Diabetes mellitus, Mammalian metabolism IntroductionDiabetes mellitus is a metabolic disease that results from a failure in glucose regulation, causing severe hyperglycemia, tissue/organ damage and increased morbidity and mortality. Pancreatic β-cells respond to high blood glucose levels by secreting the peptide hormone insulin, which acts on other tissues to promote glucose uptake from the blood, for example in the liver where it promotes energy storage by glycogen synthesis (Powers and D'Alessio, 2011). The Centers of Disease Control (CDC) estimated that 25.8 million Americans had diabetes in 2010, and more than 300 million people are affected worldwide according to the International Diabetes Federation, thus making diabetes a major worldwide healthcare challenge.Diabetes is classified into two related but distinct diseases with different causes. Type 1 diabetes results from autoimmune destruction of insulin-producing β-cells in the pancreas. Type 2 diabetes, which is commonly associated with obesity, occurs when insulin demand due to persistently high blood sugar overwhelms the capacity of β-cells to produce sufficient insulin to prevent hyperglycemia. In Type 2 diabetes, peripheral tissues, such as fat and muscle, also become resistant to the effects of insulin. This high demand on β-cells frequently leads to β-cell malfunction, dedifferentiation and death (Ashcroft and Rorsman, 2012;Talchai et al., 2012). The number of β-cells lost in Type 2 diabetes is unclear but can approach 60% (Butler et al., 2003;Rahier et al., 2008), and the remaining β-cells are likely to be in some way dysfunctional.In diabetes, the persistent misregulation of glucose homeostasis also leads to a variety of secondary complications including cardiovascular disease, retinopathy and associated blindness, neuropathy that can result in amputations, and kidney disease leading to renal failure (Powers and D'Alessio, 2011). According to the CDC, diabetes is the leading cause of kidney failure, blindness and amputations in American adults. Cardiovascular complications, whi...