In lymphopenic conditions, T cells expand to re-establish homeostasis by a process dependent on self-peptide–MHC recognition and the availability of proliferation- and survival-promoting cytokines. Although physiologically normal, chronic recurrence of this process might lead to selection of high-affinity self-reactive T-cell clones and autoimmune disease in susceptible individuals. A recent study in a diabetes-prone mouse model has provided strong evidence to support this hypothesis.