Professor Goodnow has pioneered the use of mouse molecular genetics for studying the mechanisms of immunological tolerance to self antigens. He devised a novel double-transgenic mouse strategy that revolutionised the field, confirmed the existence of B and T cell clonal energy, and revealed multiple processes for B cell and T cell clonal deletion in vivo. His work changed the conceptual framework of tolerance by showing that it is acquired through a series of regulatory checkpoints at many steps in lymphocyte maturation. The elucidation of these 'peripheral tolerance' checkpoints acting on mature and already-activated lymphocytes has fostered practical efforts to induce or restore tolerance in adults during transplantation and autoimmunity.