The thymus produces a unique lineage of cells known as CD4⁺ CD25⁺ regulatory T cells, and the exact processes leading to their development continue to be defined. Highly specific interactions between developing thymocytes and cognate self-antigens expressed by radioresistant elements in the thymus have been shown to drive CD4⁺ CD25⁺ regulatory-T-cell development. The self-peptide(s) that mediate thymic selection of CD4⁺ CD25⁺ regulatory T cells can also promote their expansion in the periphery, and self-peptides might also play a role in the conversion of CD4⁺ CD25⁻ T cells into CD25⁺ regulatory T cells.