Established memory T cell responses represent a key hurdle to both protein and tissue replacement therapies as well as the application of tolerogenic immunotherapies in general. Targeting expression of antigen to antigen-presenting cells is a powerful means to induce T-cell tolerance. We have shown previously that genetic targeting of antigens to DC and other APC inactivates memory CD4+ and CD8+ T cells, but we now show this can be exploited for induction of therapeutic tolerance to ‘turn-off’ established but unwanted T-cell responses. Here we combine the approaches of targeted antigen expression and HSCT under immune preserving conditions to show antigen-specific, therapeutic termination of memory CD4+ and CD8+ T-cell responses. The requirements for effective therapeutic tolerance induction and the mechanisms involved will be outlined.