Type 1 (insulin-dependent) diabetes mellitus (T1DM) is associated with a specific destruction of the insulin-producing beta-cells in the islets of Langerhans. Several factors, e.g. genetic, environmental and immunologial, may be involved in the etiology and pathogenesis of T1DM. Autoreactive T- and B-lymphocytes, together with macrophages infiltrate the islets during the pathogenesis, releasing a mixture of cytokines, demonstrated to be specifically toxic to the beta-cells within the islets. Our goal is to understand the molecular mechanisms responsible for the beta-cell specific toxicity enabling us to design novel intervention strategies in T1DM. The proteome approach allows us to get a detailed picture of the beta-cell proteins, which change expression level or are post-translationally modified in different in vitro and in vivo models of T1DM-associated beta-cell destruction. Combining the information obtained from this extended proteome approach, with that of genetic-, transcriptome- and candidate-gene approaches, we believe that it is possible to reach this goal.