Type 1 (insulin-dependent) diabetes mellitus results from selective immune-mediated destruction of pancreatic islet β cells. Strategies to prevent or reverse the development of diabetes can be divided into three groups, depending on whether they focus on β-cell protection, regeneration or replacement. Prevention of immune β-cell destruction involves either halting the immune attack directed against β cells or making β cells better able to withstand immune attack, for example, by making them resistant to free radical damage. The recent identification of β-cell growth factors and development of stem cell technologies provides an alternative route to the reversal of diabetes, namely β-cell regeneration. Interestingly, stem cell-derived islets appear to be less sensitive to recurrent immune destruction that is normally seen in response to islet transplantation. The last alternative is β-cell replacement or substitution. This covers a wide range of interventions including human whole pancreas transplantation, xenotransplantation, genetically modified β cells, mechanical insulin sensing and delivery devices, and the artificial pancreas. This review describes recent advances in each of these research areas and aims to provide clinicians with an idea of where and when an effective strategy to prevent or reverse diabetes development will become available.