Type 1 diabetes (T1D) appears after autoimmune processes have eradicated a large majority of the pancreatic islet β cells. Although patients may also have other organ-specific autoimmune diseases such as thyroiditis or celiac disease (CD), most T1D patients suffer from life-long insulin dependence because only the β cells have been eradicated. The genetic etiology is strongly associated with certain HLA-DQ class II heterodimers, which in part may explain the cell-specific loss as these proteins control antigen processing and presentation. Other etiologies include environmental factors such as virus and environmental or dietary toxins. The pathogenesis is closely associated with a number of autoimmune abnormalities, among them are autoantibodies and T cells to specific autoantigens. Autoantibody assays, standardized in international efforts, are used to identify autoantibodies against the islet autoantigens insulin, GAD65 and islet antigen-2 (IA-2). The presence of autoantibodies to these autoantigens predicts T1D. Other β-cell autoantigens have been reported but have failed confirmation especially because such antigens have failed to predict disease. The possible pathogenic importance of minor candidate autoantigens is typically not pursued. Reproducible and standardized T-cell tests of either CD4- or CD8-positive T cells are yet to be developed. Immunomodulating therapies with insulin and GAD65 are in progress, and preliminary data indicate that it may be possible to alter the T1D pathogenic process.