Each response made by our immune system is either to promote or to prevent immune reactivity. That the immune system can successfully achieve both goals under specific biological conditions depends on central and peripheral tolerance mechanisms. Over the years, various experimental systems have been generated to study peripheral CD4 T cell tolerance. The experimental approaches are clearly diverse, but can be broadly categorized into those involving "tolerogenic" antigen injections, the use of transgenic mice (antigen transgenics, TCR transgenics and the combination thereof) and transplantation models. Results of these studies suggested a number of potential mechanisms mediating peripheral CD4 T cell tolerance, including clonal deletion, anergy and immune regulation. While the available systems all presented with their own limitations, they nevertheless provided a foundation from which our understanding of peripheral CD4 T cell tolerance will be built. In addition, previous studies done to examine CD8 T cell tolerance left with us some potentially helpful clues and ideas about how CD4 T cell tolerance should be studied. However, our current understanding on the immunity/tolerance decision made by CD4 T cells in the periphery remains incomplete. Evidence accumulated thus far favors the view that peripheral tolerance, unlike central tolerance, may not primarily determine the selection of specificities within the baseline T cell repertoire but may instead regulate cellular responses within the repertoire, in terms of both expansion/contraction and differentiation. Nevertheless, more robust and refined models need to be developed before we can make definitive conclusions about the potential role of peripheral tolerance in repertoire selection mediated by deletion of self-reactive cells.