The loss of β-cell mass consequential to the activation of pro-apoptotic signalling events is increasingly recognised as a causal and committed stage in the development of autoimmune, type 1, diabetes mellitus (DM). While the mechanisms responsible for targeted β-cell loss are multifaceted and difficult to define at a prediabetic stage, there is a need, from a therapeutic perspective, to understand the molecular mechanisms involved. Over recent years the use of animal and cell-line models of DM, together with investigations in isolated ex vivo human islets, have greatly increased our understanding of the processes involved in the pathogenesis of type 1 DM. From this work, several biochemical pathways have emerged that may have future potential for therapeutic intervention. This review looks at the current opinions on the role of apoptosis in β-cell loss at the molecular level, focusing on a central mechanism for oxidative and nitrosative stress, and suggests biochemical pathways that may have future potential for therapeutic intervention.