The inflammatory cytokine tumor necrosis factor alpha (TNFα) has been linked to the development of several autoimmune diseases. By adapting the tetracycline-regulated gene transcription system, we generated a murine model where islet-specific expression of TNFα could be repressed/derepressed within 48 hr following introduction/removal of tetracycline in the drinking water. Here we describe the temporal importance of TNFα in diabetes development in mice expressing islet-specific B7-1 and TNFα. We show that the duration of TNFα-mediated inflammation, not the putative maturity of the immune system at the time of TNFα expression, determines diabetes progression. Further, we have described an interval between 21 and 25 days following initiation of TNFα expression where the fate of islet-reactive T cells is decided.