Whether autoimmunity results primarily from a defect of the immune system, target organ dysfunction, or both remains an open issue in most human autoimmune diseases. The highly multigenic background on which diabetes develops in the NOD mouse and in the human suggests that numerous gene variants associate in contributing to activation of autoimmunity to beta-cells. Both immune genes and islet-related genes are involved. The presence of beta-cells is required for initiation of diabetes autoimmunity to proceed. Available experiments in the NOD mouse and epidemiological evidence in the human point to proinsulin as a key autoantigen in diabetes. The functional importance of insulin, the high number of autoantigens characterized at different stages of diabetes, and their clustering within beta-cell subparticles point to the islet as a starting point in the initiation phase of the disease. Genes that direct the autoimmune reaction toward the beta-cell target, autoantigens that are recognized by autoreactive B- and T-cells along the autoimmune process, the importance of beta-cells in the activation of autoreactive lymphocytes, and the expression level of key beta-cell molecules along diabetes development are successively considered in this review.