Naturally occurring regulatory T-cells (nT-reg) are crucial in preventing generalized autoimmunity. However, antigen-specific T-reg responses during organ-specific autoimmunity have not been characterized until recently when novel tools including MHC class II-tetramers and Foxp3gfp "knock-in" reporter mice (Foxp3gfp.KI) became available. In this review, we introduce the concept of functional compartmentalisation in that T-reg may behave differently when they maintain peripheral tolerance in the secondary lymphoid tissue in a non-inflammatory environment as compared to when they are expanded and targeted to the site of inflammation following an autoantigen-specific, immunogenic stimulus.