Almost all current therapeutic approaches to inhibit destructive immune responses in autoimmunity are based on antigen non-specific agents, such as cyclosporine A, which systemically suppress the function of virtually all immune effector cells. This indiscriminate immunosuppression, however, often causes serious and sometimes life-threatening sideeffects. Indeed, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of hyperimmunosuppression such as opportunistic infections and cancer. It is evident, that treatment would be greatly improved by targeting the fundamental cause of pathogenic immune responses in autoimmunity, i.e. loss of tolerance to self-antigens. For this, manipulation of the immune system in autoimmune diseases should ideally arise in specific tolerance for the self-antigens that stimulate chronic activation of the immune system resulting in long term remissions. New – more antigen-specific and targeted therapies are intensively being investigated for the treatment of human diseases (Sabatos-Peyton et al., 2010; Dazzi et al., 2007; Miller et al., 2007). In this context, a variety of cellular therapies have been designed to elicit or amplify immune responses. These cell-based activation immunotherapies have proven to be effective for cancer and infectious diseases. Although still in its infancy, the use of well specified and functionally characterized cellular products as treatment modality for autoimmune disorders and in transplantation tolerance is gaining interest. Indeed, experiences with hematopoietic stem cells and cell types with regulatory properties support the concept of resetting immune tolerance and have made cell-based therapies for autoimmune diseases a realistic alternative. At this point however, it is not yet clear which cell type among a broad arsenal of different tolerogenic entities is best with regard to safety, efficacy and related costs. This review will explore the molecular and cellular mechanisms underlying T cell tolerance and will focus on emerging cell-based therapies pertaining to reduce, suppress or redirect existing immune responses to self-antigens in human diseases.