Gamma delta cells are attractive candidates for mediators of autoimmune disease. They can expand in germ-free mice, probably through recognition of autoantigens, and gamma delta-cell-deficient mice, unlike mice deficient in alpha beta T cells or B cells, show no severe defects in the immune response to foreign antigen challenge. A capacity of gamma delta cells to effect or regulate tissue damage is also plausible, given their ready localization to tissues, and their myriad of effector functions. Added to this, attempts to reconstruct the physiological course of autoimmune diseases with only autoreactive alpha beta T cells seem invariably to fall short for lack of other unidentified players. Gamma delta cells and their putative ligands have been linked to autoimmune conditions, and recent experiments confirm that gamma delta cells play a significant role in autoimmune disease in vivo.