Several lines of evidence suggest that premature aging of the immune system may cause alterations in the peripheral T cell homeostasis making individuals vulnerable to triggers of autoimmunity. Childhood-onset autoimmunity may offer the investigation of these aspects in the setting of a young, relatively inexperienced immune system which is affected by an imbalance in thymic output, altered proportions of peripheral T cell subpopulations and proinflammatory cytokines. One hypothesis favors the idea that premature immunosenscence in childhood-onset autoimmunity is the primary defect causing breakdown of self-tolerance; another hypothesis postulates that premature immunosenescence in children with autoimmune disorders is secondary to chronic stimulation and activation of the immune system by inflammatory processes. Population-based longitudinal studies on risk factors for development of autoimmunity beginning at infancy are required to understand the pathogenetic factors, which lead to the breakdown of self-tolerance and perpetuation of inflammation, to allow the design of targeted therapy and preventive strategies.