Although previous studies have emphasized the tolerogenic property of murine neonatal immune system, recent studies indicate that neonatal mice are prone to autoimmune disease. This chapter will summarize the evidence for neonatal propensity to autoimmune ovarian disease (AOD) and describe the new finding that autoantibody can trigger a T cell-dependent autoimmune disease in neonatal but not adult mice. Based on depletion or addition of the CD4+ CD25+ T cells, disease resistance of older mice is explicable by the emergence of CD4+ CD25+ regulatory T-cell function after day 5, whereas disease susceptibility is associated with resistance to regulation by CD4+ CD25+ T cells.