Dendritic cells (DCs) are a heterogeneous family of professional APCs involved in priming adaptive immune responses. Donor DCs (direct pathway of allorecognition) and recipient DCs presenting processed donor major histocompatibility complex (MHC) as peptides (indirect pathway of allorecognition) participate actively in graft rejection by stimulating recipient T cell responses following organ transplantation. Recent studies have shown that DCs also play a central role in inducing and maintaining tolerance to self antigens (Ags) through deletion, anergy, and regulation mechanisms. It is easy to see how the remarkable functional plasticity of DCs renders them attractive therapeutic targets for immune modulation. Indeed, in the past few years, successful outcomes in rodent models have built the case that DC-based therapy may provide a novel approach to transplant tolerance. Ongoing research into our understanding of the mechanisms whereby DCs promote tolerance in the steady-state, together with development of biologi-cally, pharmacologically and genetically manipulated ex vivo DCs to mimic/enhance their natural tolerogenicity, should warrant the success of these experimental DCs in establishing long-term allograft survival.