The lpr and gld mutations are prime examples of single-gene defects associated with expansion of a unique double-negative (CD4-8-), T-cell receptor alpha:beta + cell population and heightened polyclonal and autoimmune responses. The exact origin of these autoimmunity-inducing/enhancing T cells remains controversial. Here, we review the characteristics of the lpr and gld mutations, and speculate on the possible relationship of these cells to normal thymic differentiation pathways. We argue that mounting evidence now supports the existence of a CD4/CD8-loss pathway of late thymic differentiation, responsible for the origin of both normal and lpr/gld double-negative alpha:beta + cells. We further speculate that downregulation of CD4 and CD8 accessory molecules on thymocytes with moderately autoreactive T-cell receptors is involved in selecting cells, including lpr/gld precursors for this pathway. Escape of a large number of such autoreactive cells from thymic elimination might be an important contributory factor to the pathogenesis of autoimmunity.