We would feel quite foreign to this Forum’s discussion on “deletion and anergy”, were it not for expressing our conviction that either “models or reality” of those phenomena are not the key to understanding the physiopathology of autoimmunity. Our position is not easy to define, for we do share the notion that V-region-dependent deletion of lymphocytes operates extensively in the normal immune system. Were we not the first, after all, to describe massive bone marrow pre-B/B cell deletion in normal mice (reviewed in Coutinho et al., 1992)? And are not our theoretical models constructed around the definition of lymphocyte physiology by “bellshaped” responses to receptor occupancy, with highdose inactivation (Coutinho, 1974; Varela and Coutinho, 1991)? We strongly object, however, to simplistic views that attempt to reduce natural tolerance to deletion and/or inactivation of self-reactivities, because we have also seen many examples of positively selected functional autoreactivities in normal animals, and quite a few cases of tolerance without deletion and/or anergy of the corresponding lymphocytes. From lymphocyte physiology, we also understand that if a particular ligand concentration presented to the continuous affinity distribution of an unselected repertoire leads to deletion or inactivation of some cells, it will necessarily activate some others. If negative and positive selection are the two sides of the same coin (repertoire selection by the molecular environment of lymphocytes that respond with “bell-shaped” profiles), it is a mistake to consider only the former in the context of natural tolerance (the physiological outcome of that selection). Beyond the molecular and cellular bases of repertoire selection, self-nonself discrimination has to deal with the “origin of the ligand”, and thus with its history in the organism. To us, “single cell solutions” of a problem that concerns organisms are bound to be incomplete, or wrong. In brief, natural tolerance is a developmental question, but one of organisms and not of single lymphocytes.