Objective: Extensive research in experimental models of type 1 diabetes (T1D) has revealed the critical role of dendritic cells (DCs) in the development of the disease. Materials and Methods: + DCs (CD11c+CD11b+ and/or CD11c+CD11b-) exert aαImmature CD8 regulatory role during T cell activation against islet antigens. The steady-state immature DCs (iDCs) in the pancreas contain large amounts of unprocessed tissue antigens that in the absence of inflammation contribute to the maintenance of self tolerance and protection against diabetes. This protection correlates with increased survival of CD4+CD25+ Tregs induced by high levels of IL-7 produced by tolerogenic DCs, as well as induction of a TH2 biased + DCs produce higher levels of α CD4+ T cell response. Interestingly, CD8 - DCs in NOD mice. Moreover, α antagonistic IL-12p40 compared to CD8 costimulation-deficient DCs with a low level of CD40, CD80 and CD86 expression delay development of T1D in syngenic recipients. Results: In the light of current knowledge, several novel immunotherapy approaches have been under investigation. Costimulation-impaired DCs created by anti-sense oligonucleotides or iDCs loaded with beta cell apoptotic bodies, cytokine-treated autologous DCs and selective targeting of islet antigens to DCs are among the recently investigated methods. While DCs loaded with apoptotic bodies are resistant to LPS-mediated reexpression of costimulatory molecules, a limited number of immunizations with costimulation-deficient DCs delay the onset of T1D in NOD mice. Ex-vivo treatment of DCs with IL-4 or IL-10 renders them tolerogenic and results in a decreased incidence of T1D or even reversing the course of disease in more advanced stages. This effect is antigen-specific and is MHC class-I and MHC class-II dependent. In a more recent approach, targeted delivery of a mimotope of a beta cell peptide conjugated to a monoclonal antibody against DEC-205 endocytic receptor in NOD mice resulted in induction of CD8+ T cell tolerance which was resistant to a re-challenge with the same antigen combined with a strong adjuvant Conclusion: Mice models of T1D provide the prospect of using dendritic cells to regulate and halt the course of diabetes. However, human clinical trials have only recently been started to assess the efficiency and feasibility of these methods in the treatment of diabetes.