Herein, we succinctly review mechanisms underlying self-tolerance and the roles of dendritic leukocytes (DCs) in T-cell tolerance to self and foreign antigens. We also consider the properties of naturally arising and other populations of regulatory T cells (Treg), together with growing evidence that interplay between DCs and Treg cells can sustain antigen-specific tolerance. B-cell tolerance and the role of hematopoietic cell chimerism in the induction and maintenance of tolerance are also discussed, as is the impact of cosignaling pathway manipulation on tolerance induction. This overview also surveys prospects for technological advances in the monitoring and prediction of tolerance and the application of genomic and proteomic analysis. In addition, we consider potential novel therapeutic targets for promotion of tolerance induction.