One of the cornerstones of modern immunology is the ability of the adaptive immune system of lymphocytes to discriminate between self and nonself. Yet lymphocytes frequently make this distinction very poorly, as seen for instance by the ability to mount an adaptive immune response to self-tissues. In this brief essay on the ability to distinguish self from nonself, we will consider one model to explain how the immune system in its broader sense, including both adaptive and innate immunity, makes these distinctions reliably most of the time. Important to our argument is the fact that the receptors for these two types of immunity are encoded in fundamentally different ways. The receptors of the innate immune system are encoded in the germline, are expressed without rearrangement, and by most or all cells of a given type. They have emerged over evolutionary time, and thus are never involved in autoreactivity, because any innate immune receptor would be lethal to the host. Germline-encoded receptors for self-proteins or carbohydrates, would be rapidly removed from the germline, as they would be incompatible with life as we know it. It is also clear that in vertebrates, such germline-encoded self-reactive receptors are not observed. All autoimmune diseases thus represent adaptive immune responses against self. 1, 2 Adaptive immunity, by contrast, is encoded in rearranging gene segments. These genes must rearrange for lymphocyte development. Once both genes for a lymphocyte receptor have rearranged and are expressed on the individual cells, they are then sorted for self-nonself distinction. Depending on the type of lymphocyte, there are two processes that select the cells that are potentially autoreactive and those that are self-tolerant, which, in the case of CD4 T cells, represent about 10–50% of the