In recent years, there has been a revival of the concept of CD4(+) regulatory T (T(reg)) cells as being a central control point in various immune responses, including autoimmune responses and immunity to transplants, allergens, tumours and infectious microbes. The current literature suggests that T(reg) cells are diverse in their phenotype and mechanism(s) of action, and as such, may constitute a myriad of naturally occurring and induced T cell precursors with variable degrees of regulatory potential. In this review, we summarize research from various laboratories, including our own, showing that CD4(+)Foxp3(+) T(reg) cells are critical in the control of type 1 diabetes (T1D) in mouse models and humans. In this review, we also discuss cellular and molecular determinants that impact CD4(+)Foxp3(+) T(reg) cell development and function and consequential resistance to organ-specific autoimmune disease. Recent advances in the use of CD4(+)Foxp3(+) T(reg) cellular therapy to promote immunological tolerance in the absence of long-term generalized immunosuppression are also presented.