Type 2 diabetes is characterized by progressive beta-cell dysfunction and a reduction in beta-cell mass. Pancreatic islets are a target for adverse effectors such as high concentrations of glucose, pro-inflammatory cytokines and increased free fatty acid concentrations - which are associated with adiposity, insulin resistance and the induction of beta-cell apoptosis. If the beta-cell mass is already below the threshold for maintaining normoglycemia, the expansion of beta-cell mass is the only option for achieving normoglycemia without the use of additional glucose-lowering agents. Therapies based on glucagon-like peptide-1 and combinations of growth factors such as epidermal growth factor and gastrin are promising new strategies for beta-cell preservation. In this review, we address the mechanisms involved in beta-cell dysfunction and beta-cell loss, and provide a rationale for pharmacological intervention for the preservation and/or expansion of beta-cell mass in type 2 diabetes.