Research in organ-specific autoimmunity has been greatly facilitated over the past decade by advances in cellular and molecular immunology. Such studies have greatly expanded our understanding of autoimmune effector mechanisms and the nature of the target antigens recognized by these mediators. Another facet of organ-specific autoimmunity concerns the definition of those factors that determine host susceptibility to disease. This review outlines studies performed in two models of autoimmune interstitial nephritis that focus on issues of susceptibility and tolerance to parenchymal self antigens. In both models, antigen-specific regulatory T cells modulate the effector limb of the nephritogenic immune response and the pattern of interstitial injury. This modulation can be either stimulatory or inhibitory. The dominant regulatory effect is linked to genes in the major histocompatibility locus and is tightly correlated with disease expression. Regulatory T cells which inhibit the nephritogenic immune response can also be cultured in vitro and are highly efficacious as a therapeutic modality. These studies provide both the background and requisite reagents for delineating the mechanism(s) underlying antigen-specific T cell regulation.