Autoimmunity can occur when self-reactive lymphocytes of the adaptive immune system are activated upon encounter with antigen. This can lead to the development of debilitating and potentially life-threatening autoimmune diseases such as type-1 diabetes, rheumatoid arthritis and multiple sclerosis. Regulatory T cells (Tregs) are a subset of CD4+ T cells that express the lineage-specific transcription factor Foxp3 and exert dominant peripheral tolerance to maintain immune homeostasis. It is therefore important to fully understand the underlying mechanisms of Treg development, homeostasis and function due to the positive and negative effects that therapeutic manipulation could have on this essential T lymphocyte population. Many effector molecules have been proposed to have a central role in regulatory T cell function, and it is now clear that Tregs are equipped with multiple mechanisms by which to exert suppressive function. It has been reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor is constitutively expressed by regulatory T cells and a role for this molecule in Treg suppression has been suggested. This investigation revealed a role for CTLA-4 in maintaining homeostasis of the peripheral regulatory T cell compartment. In addition, using a transgenic mouse model that permitted the development of antigen-specific Ctla-4-deficient Tregs, a role for the CTLA-4 receptor in Treg suppressive function was identified. The data obtained suggest that the CTLA-4 receptor may function on regulatory T cells by modulating CD80/CD86 co-stimulatory molecule expression by antigen-presenting cells, and hence their capacity to activate conventional T cells to generate effector T cells and instigate an effective immune response.