Dendritic cells (DCs) are sparsely but widely distributed cells of hematopoietic origin that are specialized for the capture, processing and presentation of antigens to T cells. They also play an important role in innate immune function. DCs are heterogeneous and differ in location, migratory pathways and immunologic function. While DCs are the major cells of the immune system that promote immune response to foreign antigens, it has become increasingly clear that these antigen-presenting cells (APCs) are also involved in promoting tolerance to self-antigens. This is because DCs that carry foreign antigens from the periphery into the lymph nodes must also carry self-antigens. Based on their role in both immunity and tolerance, and their capacity to educate the various players, or effectors, in the immune response, these critical decision making cells have been called “masterminds” of the immune system.1 There is evidence supporting the concepts that both the intrinsic properties of various DCs, and their environmental context and cellular interactions affect the response outcome. In this chapter, we first review the functions of DCs, then summarize their contribution to RA and animal models of RA, and finally compare these contributions with those in some other organ-specific and systemic autoimmune diseases: type 1 diabetes and Sjögren’s syndrome and the systemic autoimmune disease systemic lupus erythematosus(SLE). What emerges from this analysis is that DCs clearly contribute in different ways to different autoimmune diseases. This has important implications for designing immunotherapy for different autoimmune diseases.