For 5 decades, immunologists have thought that during embryonic development and early life, the immune system learns to distinguish “self” antigens, which are found on the body's own tissues, from “nonself” antigens, such as invading pathogens. This idea sprang partly from experiments in which Peter Medawar showed that fetal mice can become tolerant to transplanted tissues from immunologically different donors, presumably because the neonates' immune systems accept them as self, just as they accept the animals' own tissues. But three papers in this issue have undermined the experimental basis of the self-nonself theory by showing that immunity can be induced in newborn mice under the right conditions. And conversely, tolerance can be induced in adults. The new work may not only have clinical implications, such as effective vaccines for infants or better success rates for organ transplantation, but it also opens the door to a new theory of how the immune system is activated: Instead of distinguishing self from nonself, it may spring into action when an antigen is associated with harm—the danger theory, its proponents call it.