Three hypotheses are suggested to explain the phenomenon of low responsiveness in domestic animals after injection of peptide vaccines. The first hypothesis proposes involvement of MHC haplotype and the special case in livestock breeding, where inheritance of the sire's haplotype can be closely examined by injection of antigen into a large number of paternal half‐sib progeny. The second hypothesis examines the effect of repeated antigen injections in overcoming age and MHC haplotype effects and distinguishing these effects from those caused by deficiencies in the T cell repertoire. The third hypothesis concerns non‐MHC effects that influence the expression of MHC haplotype effects and enable the host to mount an effective immune response. It is suggested that the antigen recognition signal from T cell receptor/MHC interaction is amplified to a varying extent in animal populations. Deficiency in this amplification through myeloid cell or cytokine responses may be yet another factor limiting immune responsiveness