Although the precise mechanisms involved in the establishment and maintenance of peripheral allograft tolerance are still not fully understood, it is now clear that acquisition of transplantation tolerance is an active, highly regulated, multistep process. According to the pool size model of allograft tolerance, the allograft outcome, rejection, or tolerance, often depends on the balance between cytopathic and regulatory T cells (Tregs). Although both deletion and regulation play important roles in allograft tolerance, our recent studies showed that the quantitative details for each mechanism differ from model to model. Therefore, we hypothesize that there is a delicate balance between deletion and regulation in allograft tolerance. In a model of allograft tolerance in which the deletional mechanism plays a dominant role, e.g. tolerance produced via creation of mixed chimeras, the regulatory mechanism, albeit sometimes present, is far less important. Whilst in a model in which the regulation mechanism plays a critical role, e.g. donor-specific transfusion plus MR1-induced allograft tolerance, a deletional mechanism lowers the threshold for effective Treg action.