Hyperglycemia, which is the biochemical hallmark of type 2 diabetes, mainly results from insulin resistance and beta-cell dysfunction. However, the latter is crucial in the development of the disease because diabetes cannot occur without an impairment of insulin secretion. Beta-cell failure is also responsible for progressive loss of metabolic control in type 2 diabetic patients and the eventual need for insulin treatment. An impairment of beta-cell function can be detected in several ways and can be observed already in pre-diabetic individuals. Histopathology studies documented that beta-cell volume is reduced in pre-diabetes and, to a greater extent, in type 2 diabetes mainly because the apoptotic rate of beta-cells is increased whereas neogenesis is intact. All anti-diabetic agents can improve, directly or indirectly, beta-cell function. However, only PPAR-gamma agonists and incretin-mimetic agents seem to have favorable effects on beta-cell morphology and volume. Many trials showed that type 2 diabetes can be prevented but few of them directly addressed the issue of beta-cell protection by the intervention used in the study. It is reasonable to conclude that in these trials diabetes prevention, which was based on the use of lifestyle changes (diet and/or exercise) or different drugs (tolbutamide, acarbose, metformin, glitazones, bezafibrate, orlistat, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers or pravastatin), depended also, or mainly, on a protection of the beta-cells but in most studies data on insulin secretion are not available or are insufficient to draw firm conclusions. The mechanisms of beta-cell protection in these trials, if any, remain unknown. They could be various and likely included reduced glucotoxicity, lipotoxicity, insulin resistance, inflammation, oxidant stress and/or apoptosis, an amelioration of islet blood flow and/or favorable changes in cation balance within the islets. Contrasting the decline and the eventual failure of beta-cells is crucial in preventing type 2 diabetes as well as in changing the natural history of the disease, when it occurs. The protection can be achieved in several ways but any strategy should include a change in lifestyle in order to generate a healthier islet milieu. Among anti-diabetic drugs, PPAR-gamma agonists and incretin-mimetic agents are the most promising in the protection. Among other drugs, inhibitors of the renin-angiotensin system might play a significant role. The increased worldwide diffusion of type 2 diabetes and the progressive loss of metabolic control in affected patients are clear demonstrations that the strategies to protect the beta-cells implemented so far, if any, were largely inadequate. Anti-diabetic agents targeting the intimate mechanisms of beta-cell damage might change the scenario in the near future.