The healthy host does not normally develop tissue destructive autoimmunity in part because of the presence of natural regulatory T cells. These cells are best identified by their expression of a unique transcription factor forkhead box transcription factor (Foxp3) that controls their regulatory function. Several other types of regulatory T cells also occur most of which are induced in response to antigen stimulation. Some of these express the Foxp3 transcription factor but many do not. The role of natural T-regulatory cells as well as induceable regulatory cells in autoimmunity, cancer, allergy and infectious disease is described. The current status of therapeutic approaches that modulate regulatory T-cell responses on the outcome of experimental animal and human disease is also discussed.