This study examines the molecular programmes that determine the proliferative defect of self-reactive CD8+ T cells in response to antigen; this defect is a component of peripheral tolerance. Using a T cell receptor-transgenic mouse model, the authors showed that self-reactive tolerant T cells can respond to immunization with their cognate antigen during homeostatic proliferation in lymphopenic recipients, but that these 'rescued' T cells reacquire tolerance once the hosts are lymphoreplete, even in the absence of the self antigen ('re-tolerized' T cells). Microarray analysis showed that tolerant T cells have a specific gene-expression signature, which was largely replaced by a gene signature similar to that of memory T cells in rescued T cells. Re-tolerized T cells re-established the gene signature of tolerant T cells, and the authors identified microRNA-181a as a possible key regulator of a genetic memory of tolerance.