It has recently become clear that several factors must coincide for the initiation of autoimmunity. At minimum, these involve a genetic predisposition, naïve lymphocytes that can react with autoantigens and a precipitating event that leads to T and/or B cell activation. Inter-individual variations in these factors probably explain the significant complexity associated with autoimmune diseases; however, quantitative issues are also important because clinical disease will manifest only if a sufficient amount of cellular material has been destroyed. Therefore, the presence of autoreactive lymphocytes does not always signify disease; rather, the kinetics of their generation, their resulting numbers and the regulation of their activation and effector functions (destructive versus regulatory) will determine the ultimate outcome and make the difference between subclinical autoimmunity and disease.