An emerging viewpoint states that localization of antibodies, T cells, and macrophages within the kidney occurs through specific receptor-mediated interactions to initiate nephritis. The initial events involve loss of tolerance with activation of autoreactive B cells, autoreactive T cells, or both. Many pathogenic autoantibodies form immune deposits either by binding directly to renal antigens or by complexing with endogenous antigens with affinity for renal antigens. Autoreactive T-cell infiltration requires both the presence of specific antigens and costimulatory factors expressed by cells capable of antigen presentation. It is particularly noteworthy that some of the antigen targets of the nephritogenic immune response involve either cell surface molecules or matrix components with functional properties, raising the possibility that ligation of these components could serve to modulate the local inflammatory response. Furthermore, specific perturbations within endogenous cells, resulting directly from these interactions, probably influence subsequent inflammatory-fibrogenic events. In this review, we focus on recent work relating to the loss of tolerance leading to the emergence of autoreactive B and T lymphocytes; specific autoantibody and T-cell interactions within the kidney; and the active participation of endogenous cells in the initiation of the nephritogenic response.