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Dr. Kendall Smith, the Rochelle Belfer Professor of Immunology and Medicine at Weill Cornell Medical College, reviews the progress that has been made since 1960 in our understanding of the molecules that operate to make the decisions of the immune system when contemplating whether to react or not to invasion by a foreign microbe or molecule. Because the immune system is tightly regulated by both positive and negative molecular influences, abnormalities in especially the negative regulators can lead to recognition of self as nonself and thus result in autoimmunity.