Adaptive immune responses are orchestrated by specialized professional antigen-presenting cells (APCs), the dendritic cells (DCs), which play crucial roles as initiators and modulators of adaptive immune responses. A main feature of DCs is their phenotypic and functional plasticity. In the absence of any inflammation or pathogenic elements, most DCs in peripheral tissues and lymphoid organs have a resting, immature phenotype characterized by high endocytic capacity and low surface expression of MHC- and costimulatory molecules. However, upon interaction with microbial ligands, pro-inflammatory cytokines or CD40Ligand, DCs rapidly acquire an activated phenotype. These mature DCs have a very efficient T cell-priming ability as a consequence of upregulation of MHC- and costimulatory molecules on their cell surface. For this reason, DC-based vaccines have been used successfully to combat infections and malignancies. Nonetheless, evidence is accumulating that, especially immature, or semi-matured, DCs also have a potent ability to tolerize T cells or prevent undesired immune reactions. Therefore, current and prospective strategies to promote the inherent tolerogenic potential of DCs are a rational approach for the therapy of autoimmune diseases such as rheumatoid arthritis (RA). This review summarizes some aspects of the intriguing ability of DCs to steer the outcome of immunity and their potency to modulate the outcome of various pathological conditions.