Autoreactive T cells play a major role in the pathogenesis of type 1 diabetes mellitus (T1DM) and are considered a major target of immunomodulatory strategies aimed at preventing or delaying the disease onset. However, the T-cell response against insulinproducing β cells is still poorly understood. T cells potentially able to recognize and destroy β cells are present in most individuals, but only in a few do they differentiate into pathogenic effectors. Recent and novel findings in T-cell biology on the dynamics of T-cell activation and memory maintenance are shedding new light on the general mechanisms of the T-cell response. In this article, we discuss how new discoveries about T-cell differentiation, expansion, and homeostasis could help to clarify mechanisms of autoimmunity that lead to T1DM.