A major goal in poultry immunogenetics is the enhancement of innate immunoresponsiveness and resistance to disease. This may be pursued by studying either single genes or polygenic traits. The MHC is perhaps the best-characterized family of host genes that modulates response to a variety of antigens and pathogenic challenges. The association of different MHC alleles with disease resistance has been known for decades. But only recently has analysis at the DNA level opened new avenues of understanding and new opportunities for application of genetic variation in the MHC with immunoresponsiveness. An alternate approach to molecular analysis is selection for a desired phenotype controlled by polygenes. Several studies have illustrated the successful alteration of immunoresponsiveness by genetic selection for antibody production. Recently, a selection program based upon multiple traits of immune response was conducted. Results of this project demonstrated that selection on multiple immune-response traits altered immunophysiology, MHC allelic frequencies, and disease resistance. Several areas for future pursuits in poultry immunogenetics research are proposed.