Genetic control of the immune response to staphylococcal nuclease in mice is detectable at several levels. At least one H-2-linked Ir gene controls 1) the relative proportions of antibodies to different determinants on nuclease when whole nuclease is the immunogen; 2) the immunogenicity of isolated fragments of nuclease, corresponding to the same regions or determinants; and 3) the T-lymphocyte proliferative response to nuclease and to its fragments. It is concluded that a model in which Ir-gene control is determined by the recognition by T lymphocytes of a single "carrier" determinant for the whole molecule does not adequately explain this system. Evidence is presented for the existence of more than one such H-2-linked Ir gene in the T-cell proliferative response. In addition, a non-H-2-linked gene(s) is described which controls the overall level of antibodies to nuclease, i.e., the aggregate of all the antibodies of different subspecificities which have in common that they bind to some part of the nuclease molecule. Evidence is also presented that T lymphocytes, as well as the receptors involved in Ir-gene function (whether or not these are T-lymphocyte receptors), are less sensitive to conformational differences between native nuclease and its isolated fragments than are the antibodies ultimately made. This insensitivity to conformation may reflect the recognition of determinants which are shorter or more flexible in the native state than those recognized by antibodies.