We have previously shown that the IgG response of mice to different insulins is controlled by H-2 linked Ir genes. Furthermore, the A-Chain loops of some insulins act as carrier determinants. The response to insulins is inherited as a dominant or recessive trait. More recent experiments show that in addition to H-2 linked Ir genes, other genes play an important role in the response to these antigens. (a) Complementation of two nonresponding strains to a high responding hybrid can only be achieved if at least one of the parental strains has a C3H background. (b) Induction of tolerance to the immunogenic sheep insulin can be induced by preimmunisation with the less immunogenic pig insulin only in C3H/He mice, but not other strains bearing the same H-2 haplotype. (c) A primary IgM response to pig insulin can only be induced in B10. BR but not in C3H/He mice, although both strains carry the same H-2 haplotype.